The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Noboru Taniguchi - One of the best experts on this subject based on the ideXlab platform.
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HMGB2 is a novel adipogenic factor that regulates ectopic fat infiltration in skeletal muscles
Scientific Reports, 2018Co-Authors: Deokcheol Lee, Noboru Taniguchi, Martin Lotz, Katsuaki Sato, Narantsog Choijookhuu, Yoshitaka Hishikawa, Hiroaki Kataoka, Hidetaka Morinaga, Etsuo ChosaAbstract:Although various surgical procedures have been developed for chronic rotator cuff tear repair, the re-tear rate remains high with severe fat infiltration. However, little is known about the molecular regulation of this process. Mesenchymal stem cells (MSCs) in the intra-muscular space are origin of ectopic fat cells in skeletal muscle. We have previously shown that high-mobility group box 2 (HMGB2), which is a nuclear protein commonly associated with mesenchymal differentiation, is involved in the early articular cartilage degeneration. In this study, we addressed the role of HMGB2 in adipogenesis of MSCs and fat infiltration into skeletal muscles. HMGB2 was highly expressed in undifferentiated MSCs and co-localized with platelet-derived growth factor receptor α (PDGFRA) known as an MSC-specific marker, while their expressions were decreased during adipocytic differentiation. Under the deficiency of HMGB2, the expressions of adipogenesis-related molecules were reduced, and adipogenic differentiation is substantially impaired in MSCs. Moreover, HMGB2+ cells were generated in the muscle belly of rat supraspinatus muscles after rotator cuff transection, and some of these cells expressed PDGFRA in intra-muscular spaces. Thus, our findings suggest that the enhance expression of HMGB2 induces the adipogenesis of MSCs and the fat infiltration into skeletal muscles through the cascade of HMGB2-PDGFRA.
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the new role of chromatin protein HMGB2 on adipogenesis and rotator cuff rupture
Journal of Shoulder and Elbow Surgery, 2015Co-Authors: Noboru Taniguchi, Hiroaki Yano, Yasuyuki Ishida, Naoki Suenaga, Etsuo ChosaAbstract:5 THE NEW ROLE OF CHROMATIN PROTEIN HMGB2 ON ADIPOGENESIS AND ROTATOR CUFF RUPTURE Noboru Taniguchi, Hiroaki Yano, Yasuyuki Ishida, Naoki Suenaga, Etsuo Chosa, Department of Orthopaedic Surgery, Miyazaki University, Hokushin Orthopaedic Hospital Fatty degeneration is observed in the ruptured rotator cuff, but the responsible genes for this mechanism are unknown.We have reported that chromatin protein HMGB2 is highly expressed in mesenchymal stem cells (MSC) and is involved in chondrogenesis. In this study we sought to clarify the possible role of HMGB2 on adipogenesis. We established bone marrow-derived MSC from wildtype and HMGB2-/mice and found that HMGB2-/MSC did not differentiate to adipocyte by oil-red staining and real-time PCR. DNAmicroarray analysis showed that adipogenesis related genes such as Pparg, Ppargc1a, Fabp4, and Lpl were apparently decreased in HMGB2-/MSC. HMGB2 was augmented during early adipogenic differentiation of 3T3L1 cells, and this differentiation was attenuated by gene knockdown for HMGB2. These results suggest a new role of HMGB2on adipogenesis that might regulate fatty degeneration in a ruptured rotator cuff.
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expression patterns and function of chromatin protein HMGB2 during mesenchymal stem cell differentiation
Arthritis Research & Therapy, 2012Co-Authors: Noboru Taniguchi, B Carames, Yasuhiko Kawakami, Martin LotzAbstract:The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis (OA). The expression of chromatin protein HMGB2 is restricted to the SZ, which contains cells expressing mesenchymal stem cell (MSC) markers [1]. Aging-related loss of HMGB2 and gene deletion are associated with reduced SZ cellularity and early onset OA [2]. This study addressed HMGB2 expression patterns in MSC and its role during differentiation. HMGB2 was detected at higher levels in human MSC as compared to human articular chondrocytes and its expression declined during chondrogenic differentiation of MSC (Figure (Figure1).1). Lentiviral HMGB2 transduction of MSC suppressed chondrogenesis as reflected by an inhibition of Col2a1 and Col10a1 expression. Conversely, in bone marrow MSC from HMGB2-/- mice, Col10a1 was more strongly expressed than in wildtype MSC. This is consistent with in vivo results from mouse growth plates showing that HMGB2 is expressed in proliferating and prehypertrophic zones but not in hypertrophic cartilage where Col10a1 is strongly expressed. Osteogenesis was also accelerated in HMGB2-/- MSC. The expression of Runx2, which plays a major role in late stage chondrocyte differentiation, was enhanced in HMGB2-/- MSC and HMGB2 negatively regulated the stimulatory effect of Wnt/β-catenin signaling on the Runx2 proximal promoter. Figure 1 HMGB2 expression during chondrogenesis of human MSC. Immunohistochemistry shows that HMGB2 is expressed at days 1 and 3, but that expression is reduced at days 7, 14 upon induction of chondrogenesis. SO: safranin O staining. These results demonstrate that HMGB2 expression is inversely correlated with the differentiation status of MSC and that HMGB2 suppresses chondrogenic differentiation. The aging-related loss of HMGB2 in articular cartilage may represent a mechanism responsible for the decline in adult cartilage stem cell populations.
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expression patterns and function of chromatin protein HMGB2 during mesenchymal stem cell differentiation
Journal of Biological Chemistry, 2011Co-Authors: Noboru Taniguchi, B Carames, Yasuhiko Kawakami, Emily Hsu, Stephanie Cherqui, Martin LotzAbstract:The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis (OA). The expression of chromatin protein HMGB2 is restricted to the SZ, which contains cells expressing mesenchymal stem cell (MSC) markers. Age-related loss of HMGB2 and gene deletion are associated with reduced SZ cellularity and early onset OA. This study addressed HMGB2 expression patterns in MSC and its role during differentiation. HMGB2 was detected at higher levels in human MSC as compared with human articular chondrocytes, and its expression declined during chondrogenic differentiation of MSC. Lentiviral HMGB2 transduction of MSC suppressed chondrogenesis as reflected by an inhibition of Col2a1 and Col10a1 expression. Conversely, in bone marrow MSC from HMGB2−/− mice, Col10a1 was more strongly expressed than in wild-type MSC. This is consistent with in vivo results from mouse growth plates showing that HMGB2 is expressed in proliferating and prehypertrophic zones but not in hypertrophic cartilage where Col10a1 is strongly expressed. Osteogenesis was also accelerated in HMGB2−/− MSC. The expression of Runx2, which plays a major role in late stage chondrocyte differentiation, was enhanced in HMGB2−/− MSC, and HMGB2 negatively regulated the stimulatory effect of Wnt/β-catenin signaling on the Runx2 proximal promoter. These results demonstrate that HMGB2 expression is inversely correlated with the differentiation status of MSC and that HMGB2 suppresses chondrogenic differentiation. The age-related loss of HMGB2 in articular cartilage may represent a mechanism responsible for the decline in adult cartilage stem cell populations.
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chromatin protein HMGB2 regulates articular cartilage surface maintenance via β catenin pathway
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Noboru Taniguchi, B Carames, Yasuhiko Kawakami, Brad A Amendt, Setsuro Komiya, Martin LotzAbstract:The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis. Mechanisms that regulate the unique phenotype of SZ chondrocytes and maintain SZ integrity are unknown. We recently demonstrated that expression of the chromatin protein high mobility group box (HMGB) protein 2 is restricted to the SZ in articular cartilage suggesting a transcriptional regulation involving HMGB2 in SZ. Here, we show that an interaction between HMGB2 and the Wnt/β-catenin pathway regulates the maintenance of the SZ. We found that the Wnt/β-catenin pathway is active specifically in the SZ in normal mouse knee joints and colocalizes with HMGB2. Both Wnt signaling and HMGB2 expression decrease with aging in mouse joints. Our molecular studies show that HMGB2 enhances the binding of Lef-1 to its target sequence and potentiates transcriptional activation of the Lef-1-β-catenin complex. The HMG domain within HMGB2 is crucial for interaction with Lef-1, suggesting that both HMGB2 and HMGB1 may be involved in this function. Furthermore, conditional deletion of β-catenin in cultured mouse chondrocytes induced apoptosis. These findings define a pathway where protein interactions of HMGB2 and Lef-1 enhance Wnt signaling and promote SZ chondrocyte survival. Loss of the HMGB2-Wnt signaling interaction is a new mechanism in aging-related cartilage pathology.
Martin Lotz - One of the best experts on this subject based on the ideXlab platform.
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HMGB2 is a novel adipogenic factor that regulates ectopic fat infiltration in skeletal muscles
Scientific Reports, 2018Co-Authors: Deokcheol Lee, Noboru Taniguchi, Martin Lotz, Katsuaki Sato, Narantsog Choijookhuu, Yoshitaka Hishikawa, Hiroaki Kataoka, Hidetaka Morinaga, Etsuo ChosaAbstract:Although various surgical procedures have been developed for chronic rotator cuff tear repair, the re-tear rate remains high with severe fat infiltration. However, little is known about the molecular regulation of this process. Mesenchymal stem cells (MSCs) in the intra-muscular space are origin of ectopic fat cells in skeletal muscle. We have previously shown that high-mobility group box 2 (HMGB2), which is a nuclear protein commonly associated with mesenchymal differentiation, is involved in the early articular cartilage degeneration. In this study, we addressed the role of HMGB2 in adipogenesis of MSCs and fat infiltration into skeletal muscles. HMGB2 was highly expressed in undifferentiated MSCs and co-localized with platelet-derived growth factor receptor α (PDGFRA) known as an MSC-specific marker, while their expressions were decreased during adipocytic differentiation. Under the deficiency of HMGB2, the expressions of adipogenesis-related molecules were reduced, and adipogenic differentiation is substantially impaired in MSCs. Moreover, HMGB2+ cells were generated in the muscle belly of rat supraspinatus muscles after rotator cuff transection, and some of these cells expressed PDGFRA in intra-muscular spaces. Thus, our findings suggest that the enhance expression of HMGB2 induces the adipogenesis of MSCs and the fat infiltration into skeletal muscles through the cascade of HMGB2-PDGFRA.
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antisense rna controls lrp1 sense transcript expression through interaction with a chromatin associated protein HMGB2
Cell Reports, 2015Co-Authors: Yasunari Yamanaka, Martin Lotz, Mohammad Ali Faghihi, Marco Magistri, Oscar Alvarezgarcia, Claes WahlestedtAbstract:Summary Long non-coding RNAs (lncRNAs), including natural antisense transcripts (NATs), are expressed more extensively than previously anticipated and have widespread roles in regulating gene expression. Nevertheless, the molecular mechanisms of action of the majority of NATs remain largely unknown. Here, we identify a NAT of low-density lipoprotein receptor-related protein 1 ( Lrp1 ), referred to as Lrp1- AS, that negatively regulates Lrp1 expression. We show that Lrp1- AS directly binds to high-mobility group box 2 (HMGB2) and inhibits the activity of HMGB2 to enhance Srebp1a-dependent transcription of Lrp1 . Short oligonucleotides targeting Lrp1- AS inhibit the interaction of antisense transcript and HMGB2 protein and increase Lrp1 expression by enhancing HMGB2 activity. Quantitative RT-PCR analysis of brain tissue samples from Alzheimer's disease patients and aged-matched controls revealed upregulation of LRP1-AS and downregulation of LRP1. Our data suggest a regulatory mechanism whereby a NAT interacts with a ubiquitous chromatin-associated protein to modulate its activity in a locus-specific fashion.
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expression patterns and function of chromatin protein HMGB2 during mesenchymal stem cell differentiation
Arthritis Research & Therapy, 2012Co-Authors: Noboru Taniguchi, B Carames, Yasuhiko Kawakami, Martin LotzAbstract:The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis (OA). The expression of chromatin protein HMGB2 is restricted to the SZ, which contains cells expressing mesenchymal stem cell (MSC) markers [1]. Aging-related loss of HMGB2 and gene deletion are associated with reduced SZ cellularity and early onset OA [2]. This study addressed HMGB2 expression patterns in MSC and its role during differentiation. HMGB2 was detected at higher levels in human MSC as compared to human articular chondrocytes and its expression declined during chondrogenic differentiation of MSC (Figure (Figure1).1). Lentiviral HMGB2 transduction of MSC suppressed chondrogenesis as reflected by an inhibition of Col2a1 and Col10a1 expression. Conversely, in bone marrow MSC from HMGB2-/- mice, Col10a1 was more strongly expressed than in wildtype MSC. This is consistent with in vivo results from mouse growth plates showing that HMGB2 is expressed in proliferating and prehypertrophic zones but not in hypertrophic cartilage where Col10a1 is strongly expressed. Osteogenesis was also accelerated in HMGB2-/- MSC. The expression of Runx2, which plays a major role in late stage chondrocyte differentiation, was enhanced in HMGB2-/- MSC and HMGB2 negatively regulated the stimulatory effect of Wnt/β-catenin signaling on the Runx2 proximal promoter. Figure 1 HMGB2 expression during chondrogenesis of human MSC. Immunohistochemistry shows that HMGB2 is expressed at days 1 and 3, but that expression is reduced at days 7, 14 upon induction of chondrogenesis. SO: safranin O staining. These results demonstrate that HMGB2 expression is inversely correlated with the differentiation status of MSC and that HMGB2 suppresses chondrogenic differentiation. The aging-related loss of HMGB2 in articular cartilage may represent a mechanism responsible for the decline in adult cartilage stem cell populations.
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expression patterns and function of chromatin protein HMGB2 during mesenchymal stem cell differentiation
Journal of Biological Chemistry, 2011Co-Authors: Noboru Taniguchi, B Carames, Yasuhiko Kawakami, Emily Hsu, Stephanie Cherqui, Martin LotzAbstract:The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis (OA). The expression of chromatin protein HMGB2 is restricted to the SZ, which contains cells expressing mesenchymal stem cell (MSC) markers. Age-related loss of HMGB2 and gene deletion are associated with reduced SZ cellularity and early onset OA. This study addressed HMGB2 expression patterns in MSC and its role during differentiation. HMGB2 was detected at higher levels in human MSC as compared with human articular chondrocytes, and its expression declined during chondrogenic differentiation of MSC. Lentiviral HMGB2 transduction of MSC suppressed chondrogenesis as reflected by an inhibition of Col2a1 and Col10a1 expression. Conversely, in bone marrow MSC from HMGB2−/− mice, Col10a1 was more strongly expressed than in wild-type MSC. This is consistent with in vivo results from mouse growth plates showing that HMGB2 is expressed in proliferating and prehypertrophic zones but not in hypertrophic cartilage where Col10a1 is strongly expressed. Osteogenesis was also accelerated in HMGB2−/− MSC. The expression of Runx2, which plays a major role in late stage chondrocyte differentiation, was enhanced in HMGB2−/− MSC, and HMGB2 negatively regulated the stimulatory effect of Wnt/β-catenin signaling on the Runx2 proximal promoter. These results demonstrate that HMGB2 expression is inversely correlated with the differentiation status of MSC and that HMGB2 suppresses chondrogenic differentiation. The age-related loss of HMGB2 in articular cartilage may represent a mechanism responsible for the decline in adult cartilage stem cell populations.
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chromatin protein HMGB2 regulates articular cartilage surface maintenance via β catenin pathway
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Noboru Taniguchi, B Carames, Yasuhiko Kawakami, Brad A Amendt, Setsuro Komiya, Martin LotzAbstract:The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis. Mechanisms that regulate the unique phenotype of SZ chondrocytes and maintain SZ integrity are unknown. We recently demonstrated that expression of the chromatin protein high mobility group box (HMGB) protein 2 is restricted to the SZ in articular cartilage suggesting a transcriptional regulation involving HMGB2 in SZ. Here, we show that an interaction between HMGB2 and the Wnt/β-catenin pathway regulates the maintenance of the SZ. We found that the Wnt/β-catenin pathway is active specifically in the SZ in normal mouse knee joints and colocalizes with HMGB2. Both Wnt signaling and HMGB2 expression decrease with aging in mouse joints. Our molecular studies show that HMGB2 enhances the binding of Lef-1 to its target sequence and potentiates transcriptional activation of the Lef-1-β-catenin complex. The HMG domain within HMGB2 is crucial for interaction with Lef-1, suggesting that both HMGB2 and HMGB1 may be involved in this function. Furthermore, conditional deletion of β-catenin in cultured mouse chondrocytes induced apoptosis. These findings define a pathway where protein interactions of HMGB2 and Lef-1 enhance Wnt signaling and promote SZ chondrocyte survival. Loss of the HMGB2-Wnt signaling interaction is a new mechanism in aging-related cartilage pathology.
Michal Stros - One of the best experts on this subject based on the ideXlab platform.
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nonhistone proteins hmgb1 and HMGB2 differentially modulate the response of human embryonic stem cells and the progenitor cells to the anticancer drug etoposide
Biomolecules, 2020Co-Authors: Alireza Jian Bagherpoor, Martin Kucirek, Radek Fedr, Soodabeh Abbasi Sani, Michal StrosAbstract:HMGB1 and HMGB2 proteins are abundantly expressed in human embryonic stem cells (hESCs) and hESC-derived progenitor cells (neuroectodermal cells, hNECs), though their functional roles in pluripotency and the mechanisms underlying their differentiation in response to the anticancer drug etoposide remain to be elucidated. Here, we show that HMGB1 and/or HMGB2 knockdown (KD) by shRNA in hESCs did not affect the cell stemness/pluripotency regardless of etoposide treatments, while in hESC-derived neuroectodermal cells, treatment resulted in differential effects on cell survival and the generation of rosette structures. The objective of this work was to determine whether HMGB1/2 proteins could modulate the sensitivity of hESCs and hESC-derived progenitor cells (hNECs) to etoposide. We observed that HMGB1 KD knockdown (KD) and, to a lesser extent, HMGB2 KD enhanced the sensitivity of hESCs to etoposide. Enhanced accumulation of 53BP1 on telomeres was detected by confocal microscopy in both untreated and etoposide-treated HMGB1 KD hESCs and hNECs, indicating that the loss of HMGB1 could destabilize telomeres. On the other hand, decreased accumulation of 53BP1 on telomeres in etoposide-treated HMGB2 KD hESCs (but not in HMGB2 KD hNECs) suggested that the loss of HMGB2 promoted the stability of telomeres. Etoposide treatment of hESCs resulted in a significant enhancement of telomerase activity, with the highest increase observed in the HMGB2 KD cells. Interestingly, no changes in telomerase activity were found in etoposide-treated control hNECs, but HMGB2 KD (unlike HMGB1 KD) markedly decreased telomerase activity in these cells. Changes in telomerase activity in the etoposide-treated HMGB2 KD hESCs or hNECs coincided with the appearance of DNA damage markers and could already be observed before the onset of apoptosis. Collectively, we have demonstrated that HMGB1 or HMGB2 differentially modulate the impact of etoposide treatment on human embryonic stem cells and their progenitor cells, suggesting possible strategies for the enhancement of the efficacy of this anticancer drug.
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HMGB2 is a negative regulator of telomerase activity in human embryonic stem and progenitor cells
The FASEB Journal, 2019Co-Authors: Martin Kucirek, Alireza Jian Bagherpoor, Josef Jaros, Ales Hampl, Michal StrosAbstract:High-mobility group box (HMGB)1 and HMGB2 proteins are the subject of intensive research because of their involvement in DNA replication, repair, transcription, differentiation, proliferation, cell...
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hmgb proteins interactions with dna and chromatin
Biochimica et Biophysica Acta, 2010Co-Authors: Michal StrosAbstract:HMGB proteins are members of the High Mobility Group (HMG) superfamily, possessing a unique DNA-binding domain, the HMG-box, which can bind non-B-type DNA structures (bent, kinked and unwound) with high affinity, and also distort DNA by bending/looping and unwinding. HMGBs (there are four HMGBs in mammals, HMGB1-4) are highly abundant and ubiquitously expressed non-histone proteins, acting as DNA chaperones influencing multiple processes in chromatin such as transcription, replication, recombination, DNA repair and genomic stability. Although HMGB1 is a nuclear protein, it can be secreted into the extracellular milieu as a signaling molecule when cells are under stress, in particular, when necrosis occurs. Mammalian HMGBs contain two HMG-boxes arranged in tandem, share more than 80% identity and differ in the length (HMGB1-3) or absence (HMGB4) of the acidic C-tails. The acidic tails consist of consecutive runs of only Glu/Asp residues of various length, and modulate the DNA-binding properties and functioning of HMGBs. HMGBs are subject to post-translational modifications which can fine-tune interactions of the proteins with DNA/chromatin and determine their relocation from the nucleus to the cytoplasm and secretion. Association of HMGBs with chromatin is highly dynamic, and the proteins affect the chromatin fiber as architectural factors by transient interactions with nucleosomes, displacement of histone H1, and facilitation of nucleosome remodeling and accessibility of the nucleosomal DNA to transcription factors or other sequence-specific proteins.
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hmgb1 and HMGB2 proteins up regulate cellular expression of human topoisomerase iiα
Nucleic Acids Research, 2009Co-Authors: Michal Stros, Eva Polanska, Soňa Struncova, Sarka PospisilovaAbstract:Topoisomerase IIα (topo IIα) is a nuclear enzyme involved in several critical processes, including chromosome replication, segregation and recombination. Previously we have shown that chromosomal protein HMGB1 interacts with topo IIα, and stimulates its catalytic activity. Here we show the effect of HMGB1 on the activity of the human topo IIα gene promoter in different cell lines. We demonstrate that HMGB1, but not a mutant of HMGB1 incapable of DNA bending, up-regulates the activity of the topo IIα promoter in human cells that lack functional retinoblastoma protein pRb. Transient over-expression of pRb in pRb-negative Saos-2 cells inhibits the ability of HMGB1 to activate the topo IIα promoter. The involvement of HMGB1 and its close relative, HMGB2, in modulation of activity of the topo IIα gene is further supported by knock-down of HMGB1/2, as evidenced by significantly decreased levels of topo IIα mRNA and protein. Our experiments suggest a mechanism of up-regulation of cellular expression of topo IIα by HMGB1/2 in pRb-negative cells by modulation of binding of transcription factor NF-Y to the topo IIα promoter, and the results are discussed in the framework of previously observed pRb-inactivation, and increased levels of HMGB1/2 and topo IIα in tumors.
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hmgb1 and HMGB2 cell specifically down regulate the p53 and p73 dependent sequence specific transactivation from the human bax gene promoter
Journal of Biological Chemistry, 2002Co-Authors: Michal Stros, Toshinori Ozaki, Alena Bacikova, Hajime Kageyama, Akira NakagawaraAbstract:The recently cloned genep73 is a close homologue of p53, which is a crucial tumor suppressor gene for preventing the malignant transformation of cells by inducing cell cycle arrest and apoptosis. Previous reports have shown that architectural DNA-bending/looping chromosomal proteins HMGB1 and HMGB2 (formerly known as HMG1 and HMG2), which function in a number of biological processes including transcription and DNA repair, interact in vitro with p53 and stimulate p53 binding to DNA containing p53 consensus sites. Here, we report that HMGB1 physically interacts with two splicing variants of p73, α and β (pull-down assay), and enhances binding of p73 to specific cognate DNA sites (gel-shift assay). Both HMG box domains of HMGB1, A and B, interact with p73α. Association of HMGB1 with p73, like the demonstrated ability of HMGB1 to stimulate p73 binding to different p53-responsive elements, requires the oligomerization region and/or region between DNA-binding domain and oligomerization domain of p73 (residues 312–381). Transient transfections revealed that ectopically expressed or endogenous HMGB1 and HMGB2 (antisense strategy) significantly inhibit in vivo both p73α/β- and p53-dependent transactivation from the Baxgene promoter (and much less from Mdm2 andp21waf1 promoters) in p53-deficient SAOS-2 cells. In contrast, HMGB1 and HGMB2 stimulate p73- or p53-dependent transactivation in p53-deficient H1299 cells, irrespective of the promoter used. Our results suggest that ubiquitously expressed HMGB1 and HMGB2 have potential tocell- and promoter-specifically down- or up-regulate in vivo transcriptional activity of different members of the p53 family. A possible mechanism of HMGB1-mediated modulation of p73- and p53-dependent transactivation is discussed.
Marco Bianchi - One of the best experts on this subject based on the ideXlab platform.
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aging related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Noboru Taniguchi, Lorenza Ronfani, Marco Bianchi, B Carames, Setsuro Komiya, Ulrich Ulmer, Martin LotzAbstract:Osteoarthritis (OA) is the most common joint disease and typically begins with an aging-related disruption of the articular cartilage surface. Mechanisms leading to the aging-related cartilage surface degeneration remain to be determined. Here, we demonstrate that nonhistone chromatin protein high-mobility group box (HMGB) protein 2 is uniquely expressed in the superficial zone (SZ) of human articular cartilage. In human and murine cartilage, there is an aging-related loss of HMGB2 expression, ultimately leading to its complete absence. Mice genetically deficient in HMGB2 (HMGB2−/−) show earlier onset of and more severe OA. This is associated with a profound reduction in cartilage cellularity attributable to increased cell death. These cellular changes precede glycosaminoglycan depletion and progressive cartilage erosions. Chondrocytes from HMGB2−/− mice are more susceptible to apoptosis induction in vitro. In conclusion, HMGB2 is a transcriptional regulator specifically expressed in the SZ of human articular cartilage and supports chondrocyte survival. Aging is associated with a loss of HMGB2 expression and reduced cellularity, and this contributes to the development of OA.
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the long acidic tail of high mobility group box 1 hmgb1 protein forms an extended and flexible structure that interacts with specific residues within and between the hmg boxes
Biochemistry, 2004Co-Authors: S Knapp, Susanne Muller, Tiziana Bonaldi, Marco Bianchi, Giuseppe Digilio, Giovanna MuscoAbstract:HMGB1 (high mobility group B1) is a conserved chromosomal protein composed of two similar DNA binding domains (HMG box A and box B) linked by a short basic stretch to an acidic C-terminal tail of 30 residues. The acidic tail modulates the DNA binding properties of HMGB1, and its length differentiates the various HMGB family members. We synthesized a peptide that corresponds to the acidic tail in HMGB1 (T-peptide) and studied its binding to the single boxes and to the fragment corresponding to tailless HMGB1 (designated as ABbt fragment). CD spectroscopy showed that T-peptide stabilizes significantly the ABbt fragment and that the complex has an identical thermal stability as full-length HMGB1. Calorimetric and NMR data showed that T-peptide binds with a dissociation constant of 9 μM to box A and much more weakly to box B. 1H−15N HSQC spectra of full-length HMGB1 and of the ABbt fragment are very similar; the small chemical shift differences that exist correspond to those residues of the ABbt fragment that...
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association of chromatin proteins high mobility group box hmgb 1 and HMGB2 with mitotic chromosomes
Molecular Biology of the Cell, 2003Co-Authors: Coralie Pallier, Paola Scaffidi, Alessandra Agresti, Marco Bianchi, Stephanie Chopineauproust, Patrice Nordmann, Vincent MarechalAbstract:High mobility group box (HMGB) 1 and 2 are two abundant nonhistone nuclear proteins that have been found in association with chromatin. Previous studies based on immunofluorescence analysis indicat...
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a nuclear protein complex containing high mobility group proteins b1 and b2 heat shock cognate protein 70 erp60 and glyceraldehyde 3 phosphate dehydrogenase is involved in the cytotoxic response to dna modified by incorporation of anticancer nucleosi
Cancer Research, 2003Co-Authors: Eugene Y Krynetski, Marco Bianchi, Natalia F Krynetskaia, William E EvansAbstract:Thiopurine treatment of human leukemia cells deficient in components of the mismatch repair system (Nalm6) initiated apoptosis after incorporation into DNA, as revealed by caspase activation and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. To elucidate the cellular sensor(s) responsible for recognition of DNA damage in cells with an inactive mismatch repair system, we isolated a multiprotein nuclear complex that preferentially binds DNA with thioguanine incorporated. The components of this nuclear multiprotein complex, as identified by protein mass spectroscopy, included high mobility group proteins 1 and 2 (HMGB1, HMGB2), heat shock protein HSC70, protein disulfide isomerase ERp60, and glyceraldehyde 3-phosphate dehydrogenase. The same complex was also shown to bind synthetic oligodeoxyribonucleotide duplexes containing the nonnatural nucleosides 1-beta-D-arabinofuranosylcytosine or 5-fluoro-2'-deoxyuridine. Fibroblast cell line derived from Hmgb1(-/-) murine embryos had decreased sensitivity to thiopurines, with an IC(50) 10-fold greater than Hmgb1-proficient cells (P < 0.0001) and exhibited comparable sensitivity to vincristine, a cytotoxic drug that is not incorporated into DNA. These findings indicate that the HMGB1-HMGB2-HSC70-ERp60-glyceraldehyde 3-phosphate dehydrogenase complex detects changes in DNA structure caused by incorporation of nonnatural nucleosides and is a determinant of cell sensitivity to such DNA modifying chemotherapy.
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the double life of hmgb1 chromatin protein architectural factor and extracellular signal
The EMBO Journal, 2001Co-Authors: Susanne Muller, Paola Scaffidi, Bernard Degryse, Tiziana Bonaldi, Lorenza Ronfani, Alessandra Agresti, Monica Beltrame, Marco BianchiAbstract:The High Mobility Group Box (HMGB) chromosomal proteins have been known and studied for a long time, but we have only recently started to understand their biological functions. They now have a clear reputation for being important architectural factors: they facilitate the assembly of site‐specific DNA binding proteins to their cognate binding sites within chromatin. Beyond this intranuclear function, they also have an extracellular function, which will be the prime focus of this short review. ### The HMGB family: structure, expression and nuclear function The HMGB family comprises the three proteins HMGB1 (previously HMG1), HMGB2 (previously HMG2) and HMGB3 (previously HMG4 or HMG2b) (Bustin, 2001). The structure of these three proteins is highly conserved (>80% amino acid identity), and their biochemical properties are so far indistinguishable. HMGBs are composed of three different domains. The two homologous DNA binding domains, HMG boxes A and B, are each ∼75 amino acids in length. The C‐terminal domain is highly negatively charged, consisting of a continuous stretch of glutamate or aspartate residues, and is longest in HMGB1 and shortest in HMGB3 (reviewed in Bustin, 1999; Bianchi and Beltrame, 2000). HMGB1 is ubiquitous and only 10 times less abundant than core histones, at ∼106 molecules per typical mammalian cell. Expression of the other two family members is more restricted: HMGB3 is only expressed to a significant amount during embryogenesis (Vaccari et al ., 1998); HMGB2 is widely expressed during embryonic development, but restricted mainly to lymphoid organs and testis in the adult mouse (Ronfani et al ., 2001). The localization of these proteins in most cells is nuclear. In their nuclear identity, HMGB1 and HMGB2 bind to the minor groove of DNA, causing a local distortion of the double helix. They have little or no sequence preference, and they are recruited to the site of action by specific DNA binding proteins. HMGB1 has …
Anne Zirkel - One of the best experts on this subject based on the ideXlab platform.
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HMGB2 loss upon senescence entry disrupts genomic organization and induces ctcf clustering across cell types
Molecular Cell, 2018Co-Authors: Anne Zirkel, Milos Nikolic, Konstantinos Sofiadis, Janphilipp Mallm, Chris A Brackley, Henrike Johanna Gothe, Oliver Drechsel, Christian Becker, Janine Altmuller, Natasa JosipovicAbstract:Summary Processes like cellular senescence are characterized by complex events giving rise to heterogeneous cell populations. However, the early molecular events driving this cascade remain elusive. We hypothesized that senescence entry is triggered by an early disruption of the cells' three-dimensional (3D) genome organization. To test this, we combined Hi-C, single-cell and population transcriptomics, imaging, and in silico modeling of three distinct cells types entering senescence. Genes involved in DNA conformation maintenance are suppressed upon senescence entry across all cell types. We show that nuclear depletion of the abundant HMGB2 protein occurs early on the path to senescence and coincides with the dramatic spatial clustering of CT CF. Knocking down HMGB2 suffices for senescence-induced CTCF clustering and for loop reshuffling, while ectopically expressing HMGB2 rescues these effects. Our data suggest that HMGB2-mediated genomic reorganization constitutes a primer for the ensuing senescent program.
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HMGB2 loss upon senescence entry disrupts genomic organization and induces ctcf clustering across cell types
Social Science Research Network, 2018Co-Authors: Anne Zirkel, Milos Nikolic, Konstantinos Sofiadis, Janphilipp Mallm, Chris A Brackley, Henrike Johanna Gothe, Oliver Drechsel, Christian Becker, Janine Altmuller, Theodore GeorgomanolisAbstract:Ageing-relevant processes, like cellular senescence, are characterized by complex events giving rise to heterogeneous cell populations. However, the early molecular events that trigger such cascades remain elusive. We hypothesized that senescence entry by primary human cells is characterized by an early disruption of the cells' three-dimensional genome organization. To test this, we combined Hi-C, single-cell and population transcriptomics, super-resolution imaging, in silico simulations, and functional analyses on proliferating and replicatively-senescent cells from three distinct lineages. We discovered a cluster of genes involved in DNA conformation maintenance being suppressed upon senescence entry across all cell types. Of these, the abundant non-histone-like HMGB2 is depleted from nuclei before typical senescence markers appear, and is involved in loop formation. Its loss coincides with a reorganization of chromatin interactions via dramatic spatial clustering of CTCF foci. Upon HMGB2 knock-down this senescence-induced CTCF clustering is recapitulated and CTCF loops are reshuffled, as HMGB2 appears to confer local insulation both at TAD boundaries and within TADs. Our data suggest that the HMGB-mediated deregulation of genomic organization constitutes a primer for the ensuing senescent program across cell lineages.
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topological demarcation by HMGB2 is disrupted early upon senescence entry across cell types and induces ctcf clustering
bioRxiv, 2017Co-Authors: Anne Zirkel, Milos Nikolic, Konstantinos Sofiadis, Janphilipp Mallm, Christian Becker, Lilija Brant, Janine Altmueller, Julia Franzen, Mirjam Koker, Eduardo G GusmaoAbstract:Ageing-relevant processes, like cellular senescence, are characterized by complex, often stochastic, events giving rise to heterogeneous cell populations. We hypothesized that entry into senescence of different primary human cells can be triggered by one early molecular event affecting the spatial organization of chromosomes. To test this, we combined whole-genome chromosome conformation capture, population and single-cell transcriptomics, super-resolution imaging, and functional analyses applied on proliferating and replicatively-senescent populations from three distinct human cell types. We found a number of genes involved in DNA conformation maintenance being suppressed upon senescence across cell types. Of these, the abundant high mobility group (HMG) B1 and B2 nuclear factors are quantitatively removed from cell nuclei before typical senescence markers appear, and mark a subset of topologically-associating domain (TAD) boundaries. Their loss coincides with obvious reorganization of chromatin interactions via the dramatic spatial clustering of CTCF foci. HMGB2 knock-down recapitulates this senescence-induced CTCF clustering, while also affecting insulation at TAD boundaries. We accordingly propose that HMGB-mediated deregulation of chromosome conformation constitutes a primer for the ensuing senescent program across cell types.