Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: a novel mechanism of human osteoarthritis cartilage degeneration

In up to 15% of acute myeloid leukemias (AMLs), a recurring chromosomal translocation, termed t(8;21), generates the AML1–eight–twenty-one (ETO) leukemia fusion protein, which contains the DNA-binding domain of Runt-related transcription factor 1 (RUNX1) and almost all of ETO. RUNX1 and the AML1–ETO fusion protein are coexpressed in t(8;21) AML cells and antagonize each other's gene-regulatory functions. AML1–ETO represses transcription of RUNX1 target genes by competitively displacing RUNX1 and recruiting corepressors such as histone deacetylase 3 (HDAC3). Recent studies have shown that AML1–ETO and RUNX1 co-occupy the binding sites of AML1–ETO–activated genes. How this joined binding allows RUNX1 to antagonize AML1–ETO–mediated transcriptional activation is unclear. Here we show that RUNX1 functions as a bona fide repressor of transcription activated by AML1–ETO. Mechanistically, we show that RUNX1 is a component of the HDAC3 corepressor complex and that HDAC3 preferentially binds to RUNX1 rather than to AML1–ETO in t(8;21) AML cells. Studying the regulation of interleukin-8 (IL8), a newly identified AML1–ETO–activated gene, we demonstrate that RUNX1 and HDAC3 collaboratively repress AML1–ETO–dependent transcription, a finding further supported by results of genome-wide analyses of AML1–ETO–activated genes. These and other results from the genome-wide studies also have important implications for the mechanistic understanding of gene-specific coactivator and corepressor functions across the AML1–ETO/RUNX1 cistrome.

Download Full-text

Regulation of MEF2 by Histone Deacetylase 4- and SIRT1 Deacetylase-Mediated Lysine Modifications

Molecular and Cellular Biology ◽

10.1128/mcb.25.19.8456-8464.2005 ◽

2005 ◽

Vol 25 (19) ◽

pp. 8456-8464 ◽

Cited By ~ 189

Author(s):

Xuan Zhao ◽

Thomas Sternsdorf ◽

Timothy A. Bolger ◽

Ronald M. Evans ◽

Tso-Pang Yao

Keyword(s):

Transcription Factor ◽

Histone Deacetylase ◽

Transcriptional Activity ◽

Histone Deacetylation ◽

Muscle Cell Differentiation ◽

Histone Deacetylase 4 ◽

Reconstituted System ◽

Sumo E3 Ligase

ABSTRACT The class II deacetylase histone deacetylase 4 (HDAC4) negatively regulates the transcription factor MEF2. HDAC4 is believed to repress MEF2 transcriptional activity by binding to MEF2 and catalyzing local histone deacetylation. Here we report that HDAC4 also controls MEF2 by a novel SUMO E3 ligase activity. We show that HDAC4 interacts with the SUMO E2 conjugating enzyme Ubc9 and is itself sumoylated. The overexpression of HDAC4 leads to prominent MEF2 sumoylation in vivo, whereas recombinant HDAC4 stimulates MEF2 sumoylation in a reconstituted system in vitro. Importantly, HDAC4 promotes sumoylation on a lysine residue that is also subject to acetylation by a MEF2 coactivator, the acetyltransferase CBP, suggesting a possible interplay between acetylation and sumoylation in regulating MEF2 activity. Indeed, MEF2 acetylation is correlated with MEF2 activation and dynamically induced upon muscle cell differentiation, while sumoylation inhibits MEF2 transcriptional activity. Unexpectedly, we found that HDAC4 does not function as a MEF2 deacetylase. Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation. Our studies reveal a novel regulation of MEF2 transcriptional activity by two distinct classes of deacetylases that affect MEF2 sumoylation and acetylation.

Download Full-text

Histone deacetylase inhibition leads to regulatory histone mark alterations and impairs meiosis in oocytes

Epigenetics & Chromatin ◽

10.1186/s13072-021-00413-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Louis Legoff ◽

Ouzna Dali ◽

Elena De La Mata Santaella ◽

Christian Jaulin ◽

Shereen Cynthia D’Cruz ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Histone Deacetylase ◽

Epigenetic Marks ◽

Histone Deacetylase Inhibition ◽

Expression Of Genes ◽

Germ Cell Specification ◽

Genes Encoding ◽

Related Transcription Factor ◽

Inhibitor Drug

Abstract Background Panobinostat (PB), a histone deacetylase (HDAC) inhibitor drug, is clinically used in the treatment of cancers. We investigated the effects of PB on murine ovarian functions in embryos and adult animals. Methods C57BL/6J mice were treated with 5 mg/kg PB on alternate days from embryonic day (E) 6.5 to E15.5. We analysed the effects of PB on the ovaries by using immunofluorescence, gene expression analysis and DNA methylation analysis techniques. Results At E15.5, we observed increases in histone H3K9Ac, H4Ac and H3K4me3 marks, while the level of the silencing H3K9me3 mark decreased. Synaptonemal complex examination at E15.5, E17.5 and E18.5 showed a delay in meiotic progression characterized by the absence of synaptonemal complexes at E15.5 and the persistence of double-strand breaks (DSBs) at E17.5 and E18.5 in PB-exposed oocytes. We found that exposure to PB led to changes in the expression of 1169 transcripts at E15.5. Genes regulated by the male-specific factors SRY-Box Transcription Factor 9 (SOX9) and Doublesex and Mab-3-related Transcription factor 1 (DMRT1) were among the most upregulated genes in the ovaries of PB-exposed mice. In contrast, PB treatment led to decreases in the expression of genes regulated by the WNT4 pathway. Notably, we observed 119 deregulated genes encoding Zn-finger proteins. The observed alterations in epigenetic marks and gene expression correlated with decreases in the numbers of germ cells at E15.5. After birth, PB-exposed ovaries showed increased proliferation of primary and secondary follicles. We also observed decreases in the numbers of primordial, primary and secondary follicles in adult ovaries from mice that were exposed to PB in utero. Finally, epigenetic alterations such as decreased H3K4me3 and increased H4 acetylation levels were also detected in somatic cells surrounding fully grown oocytes. Conclusion Our data suggest that inhibition of histone deacetylase by PB during a critical developmental window affects reprogramming and germ cell specification via alteration of epigenetic marks.

Download Full-text

HDAC4 mutant represses chondrocyte hypertrophy by locating in the nucleus and attenuates disease progression of posttraumatic osteoarthritis

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04947-6 ◽

2022 ◽

Vol 23 (1) ◽

Author(s):

Xiaodong Gu ◽

Fei Li ◽

Yangyang Gao ◽

Xianda Che ◽

Pengcui Li

Keyword(s):

Articular Cartilage ◽

Histone Deacetylase ◽

Cartilage Damage ◽

Adenovirus Vector ◽

Cartilage Degeneration ◽

Sprague Dawley ◽

Chondrocyte Hypertrophy ◽

Sprague Dawley Rats ◽

Histone Deacetylase 4 ◽

Safranin O

Abstract Background The aim of this study was to evaluate whether histone deacetylase 4 S246/467/632A mutant (m-HDAC4) has enhanced function at histone deacetylase 4 (HDAC4) to attenuate cartilage degeneration in a rat model of osteoarthritis (OA). Methods Chondrocytes were infected with Ad-m-HDAC4-GFP or Ad-HDAC4-GFP for 24 h, incubated with interleukin-1β (IL-1β 10 ng/mL) for 24 h, and then measured by RT-qPCR. Male Sprague-Dawley rats (n = 48) were randomly divided into four groups and transduced with different vectors: ACLT/Ad-GFP, ACLT/Ad-HDAC4-GFP, ACLT/Ad-m-HDAC4-GFP, and sham/Ad-GFP. All rats received intra-articular injections 48 h after the operation and every 3 weeks thereafter. Cartilage damage was assessed using radiography and Safranin O staining and quantified using the OARSI score. The hypertrophic and anabolic molecules were detected by immunohistochemistry and RT-qPCR. Results M-HDAC4 decreased the expression levels of Runx-2, Mmp-13, and Col 10a1, but increased the levels of Col 2a1 and ACAN more effectively than HDAC4 in the IL-1β-induced chondrocyte OA model; upregulation of HDAC4 and m-HDAC4 in the rat OA model suppressed Runx-2 and MMP-13 production, and enhanced Col 2a1 and ACAN synthesis. Stronger Safranin O staining was detected in rats treated with m-HDAC4 than in those treated with HDAC4. The resulting OARSI scores were lower in the Ad-m-HDAC4 group (5.80 ± 0.45) than in the Ad-HDAC4 group (9.67 ± 1.83, P = 0.045). The OARSI scores were highest in rat knees that underwent ACLT treated with Ad-GFP control adenovirus vector (14.93 ± 2.14, P = 0.019 compared with Ad-HDAC4 group; P = 0.003 compared with Ad-m-HDAC4 group). Lower Runx-2 and MMP-13 production, and stronger Col 2a1 and ACAN synthesis were detected in rats treated with m-HDAC4 than in those treated with HDAC4. Conclusions M-HDAC4 repressed chondrocyte hypertrophy and induced chondrocyte anabolism in the nucleus. M-HDAC4 was more effective in attenuating articular cartilage damage than HDAC4.

Download Full-text

Functional characterization of the regulation of transcription factor MEF2C by histone acetyltransferase p300 and histone deacetylase 4

10.14711/thesis-b839591 ◽

2004 ◽

Author(s):

Jonathan Ka Lok Chan

Keyword(s):

Transcription Factor ◽

Histone Deacetylase ◽

Histone Acetyltransferase ◽

Functional Characterization ◽

Regulation Of Transcription ◽

Histone Deacetylase 4 ◽

Acetyltransferase P300

Download Full-text

Subcellular relocation of histone deacetylase 4 regulates growth plate chondrocyte differentiation through Ca2+/calmodulin-dependent kinase IV

AJP Cell Physiology ◽

10.1152/ajpcell.00348.2011 ◽

2012 ◽

Vol 303 (1) ◽

pp. C33-C40 ◽

Cited By ~ 20

Author(s):

Yingjie Guan ◽

Qian Chen ◽

Xu Yang ◽

Paul Haines ◽

Ming Pei ◽

...

Keyword(s):

Histone Deacetylase ◽

Growth Plate ◽

Chondrocyte Differentiation ◽

Differentiation Markers ◽

Proliferation Zone ◽

Primary Chondrocytes ◽

Related Transcription Factor ◽

Histone Deacetylase 4 ◽

Increased Activity

Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that histone deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca2+/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation.

Download Full-text