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A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [II]

ABSTRACT: Purpose: Identification of SEs in time course after HDAC4 depletion and correlation to the accumulation of DNA damage. Outcome: We discovered a novel epigenetic complex formed by HDAC4 and HDAC2 that is involved in the erasure of H2BK120 acetylation. The HDAC4/HDAC2 complex, through the dynamic deacetylation of H2BK120, modulates the efficiency of DNA repair by homologous recombination (HR) by controlling the recruitment of BRCA1 and CtIP to the site of lesions. Degradation of HDAC4 during senescence has a dual effect. First, it contributes to super-enhancers activation by limiting HDAC3 activity, and second, it causes the accumulation of damaged DNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216861 | GEO | 2024/06/18

REPOSITORIES: GEO

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A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [I]

Project description:Purpose: Recognize the specific H2BK120ac profile around HDAC4 binding sites in proliferating, pre-senescent, senescent and senescence escaped cells during the accumulation of dsDNA damage, compared to undamaged regions. Outcome: We discovered a novel epigenetic complex formed by HDAC4 and HDAC2 that is involved in monitoring H2BK120 acetylation. The HDAC4/HDAC2 complex, through the dynamic deacetylation of H2BK120, modulates the efficiency of DNA repair by homologous recombination (HR) by controlling the recruitment of BRCA1 and CtIP to the site of lesions. Degradation of HDAC4 during senescence has a dual effect. First, it contributes to super-enhancers activation by limiting HDAC3 activity, and second, it causes the accumulation of DNA damage.

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Project description:Access to DNA is the first level of control in regulating gene transcription, a control that is also critical for maintaining DNA integrity. Cellular senescence is characterized by profound transcriptional rearrangements and accumulation of DNA lesions. Here, we discovered an epigenetic complex between HDAC4 and HDAC1/HDAC2 that is involved in the erase of H2BK120 acetylation. The HDAC4/HDAC1/HDAC2 complex modulates the efficiency of DNA repair by homologous recombination, through dynamic deacetylation of H2BK120. Deficiency of HDAC4 leads to accumulation of H2BK120ac, impaired recruitment of BRCA1 and CtIP to the site of lesions, accumulation of damaged DNA and senescence. In senescent cells this complex is disassembled because of increased proteasomal degradation of HDAC4. Forced expression of HDAC4 during RAS-induced senescence reduces the genomic spread of γH2AX and affects H2BK120ac levels, which are increased in DNA-damaged regions accumulated during RAS-induced senescence. In summary, degradation of HDAC4 during senescence causes the accumulation of damaged DNA and contributes to the activation of the transcriptional program controlled by super-enhancers that maintains senescence.

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A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation

Project description:A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation

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A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [II]

Project description:A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [II]

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A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [I]

Project description:A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [I]

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HDAC4 controls senescence and aging by safeguarding the epigenetic identity and ensuring the genomic integrity

Project description:Purpose: Define HDAC4 signature Outcome: HDAC4 is required for the repression of a senescence signature. HDAC4 KO promotes the expression of inflammatory genes, the derepression of ERVs and the accumulation of DNA damage. All together these signalling pathways lead to permanent cell-cycle arrest in low grade tumor cells and pre-transformation models, while they weaken the replicative potential of primary normal cells.

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HDAC4 influences the DNA damage response and counteracts senescence by assembling with HDAC1/HDAC2 to control H2BK120 acetylation and homology-directed repair.

Project description:Access to DNA is the first level of control in regulating gene transcription, a control that is also critical for maintaining DNA integrity. Cellular senescence is characterized by profound transcriptional rearrangements and accumulation of DNA lesions. Here, we discovered an epigenetic complex between HDAC4 and HDAC1/HDAC2 that is involved in the erase of H2BK120 acetylation. The HDAC4/HDAC1/HDAC2 complex modulates the efficiency of DNA repair by homologous recombination, through dynamic deacetylation of H2BK120. Deficiency of HDAC4 leads to accumulation of H2BK120ac, impaired recruitment of BRCA1 and CtIP to the site of lesions, accumulation of damaged DNA and senescence. In senescent cells this complex is disassembled because of increased proteasomal degradation of HDAC4. Forced expression of HDAC4 during RAS-induced senescence reduces the genomic spread of γH2AX. It also affects H2BK120ac levels, which are increased in DNA-damaged regions that accumulate during RAS-induced senescence. In summary, degradation of HDAC4 during senescence causes the accumulation of damaged DNA and contributes to the activation of the transcriptional program controlled by super-enhancers that maintains senescence.

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A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation

Project description:This SuperSeries is composed of the SubSeries listed below.

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Nociceptor HDAC4 regulates inflammatory pain

Project description:Transcriptional alterations are characteristic of persistent pain states but the key regulators remain elusive. Using a conditional knockout (cKO) strategy in mice we sought to determine whether loss of the transcriptional co-repressor histone deacetylase four (HDAC4) would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely dispensable for transcriptional regulation of naïve sensory neurons but was required for transcriptional responses after injury, with Calca and Trpv1 expression consistently downregulated in HDAC4 cKO compared to littermate controls (0.2-0.44 fold). This downregulation corresponded to reduced sensitivity to capsaicin in vitro (76% +/- 4.4% wildtype capsaicin responders vs 56.9% +/- 4.7% cKO responders) and to reduced thermal hypersensitivity in the complete Freund’s adjuvant model of inflammatory pain (1.3-1.4 fold improvement). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors. Total RNA was extracted from HDAC4 cKO and HDAC4 fl/fl naïve adult lumbar dorsal root ganglia (n=3/group). mRNA expression was compared using Affymetrix Mouse Gene Arrays (Mouse Gene 2.0ST) run on a GeneChip Fluidics Station 450. Chips were scanned on an Affymetrix GeneChip Scanner.

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