Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery

Greer, Celeste B.; Tanaka, Yoshiaki; Kim, Yoonjung; Xie, Peng; Zhang, Michael Qiwei; Park, In Hyun; Kim, Tae Hoon

doi:10.1016/j.celrep.2015.10.013

Cited by 146 publications

(163 citation statements)

References 61 publications

Supporting

Mentioning

151

Contrasting

Order By: Relevance

“…HDACs may act not only through modulation of chromatin but also by changing the properties of transcription factors, collectively resulting in activation or repression (Baltus et al, 2009a; Greer et al, 2015; Incani et al, 2014; Wang et al, 2009; Yao et al, 2001). In this context, we asked whether Hdac2 affects SoxB2 mRNA and/or protein levels.…”

Section: Resultsmentioning

confidence: 99%

An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian

et al. 2017

View full text Add to dashboard Cite

SUMMARY SoxB transcription factors and histone deacetylases (HDACs) are each major players in the regulation of neurogenesis, but a functional link between them has not been previously demonstrated. Here, we show that SoxB2 and Hdac2 act together to regulate neurogenesis in the cnidarian Hydractinia echinata during tissue homeostasis and head regeneration. We find that misexpression of SoxB genes modifies the number of neural cells in all life stages and interferes with head regeneration. Hdac2 was co-expressed with SoxB2 and its down-regulation phenocopied SoxB2 knockdown. We also show that SoxB2 and Hdac2 promote each other's transcript levels, but Hdac2 counteracts this amplification cycle by deacetylating and destabilizing SoxB2 protein. Finally, we present evidence for conservation of these interactions in human neural progenitors. We hypothesize that crosstalk between SoxB transcription factors and Hdac2 is an ancient feature of metazoan neurogenesis and functions to stabilize the correct levels of these multifunctional proteins.

show abstract

Section: Resultsmentioning

confidence: 99%

An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Hdac3 deletion resulted in the increased expression of 356 genes (Fig. 3A) although slightly more genes showed downregulation upon Hdac3 deletion (26). Among those genes significantly up-regulated upon Hdac3 loss were critical regulators of B-cell development, including Rag1, Rag2, terminal deoxynucleotidyl transferase (encoded by Dntt), and Pax5, which are required for VDJ recombination (Fig.…”

Section: Cd43mentioning

confidence: 99%

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

Stengel

Barnett

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Histone deacetylase 3 (HDAC3) is the catalytic component of NCoR/SMRT corepressor complexes that mediate the actions of transcription factors implicated in the regulation of B-cell development and function. We crossed Hdac3 conditional knockout mice with Mb1-Cre knockin animals to delete Hdac3 in early progenitor B cells. The spleens of Hdac3 CD43+ populations identified a defect in V H DJ H recombination with a severe reduction in productive rearrangements, which directly corresponded to the loss of pre-B cells from Hdac3 Δ/− bone marrow. For Hdac3 Δ/− B cells that did show productive VDJ rearrangement, there was significant skewing toward the incorporation of proximal V H gene segments and a corresponding reduction in distal V H gene segment use. Although transcriptional effects within these loci were modest, Hdac3 Δ/− progenitor cells displayed global changes in chromatin structure that likely hindered effective distal V-DJ recombination. Reintroduction of wild-type Hdac3 restored normal B-cell development, whereas an Hdac3 point mutant lacking deacetylase activity failed to complement this defect. Thus, the deacetylase activity of Hdac3 is required for the generation of mature B cells.istone deacetylase 3 (Hdac3) functions as the catalytic component of NCoR/SMRT corepressor complexes that are recruited by sequence-specific transcription factors to regulate transcription through the deacetylation of both histone and nonhistone proteins (1-3). Although bulk histone acetylation is generally controlled during replication by Hdac1 and Hdac2 (4, 5), Hdac3 is required for the maintenance of heterochromatin in some tissues (6, 7). Furthermore, the ability of Hdac3 to modulate chromatin accessibility has profound effects on gene transcription, DNA replication, and DNA repair (8-13). For example, hepatocyte-specific deletion of Hdac3 resulted in global changes in histone acetylation, nucleosomal compaction, and changes in gene expression (6). Although Hdac3 has robust deacetylase activity and is proposed to mediate the activity of some class II HDACs that lack intrinsic deacetylase function (14, 15), deacetylase inactive mutants of Hdac3 appeared to partially complement the phenotype of hepatocyte-specific Hdac3-knockout mice (16). This was interesting given that the livers of Albumin-Cre-Hdac3 −/− mice displayed phenotypes associated with global increases in histone acetylation, including a loss of heterochromatin (6, 9).The adaptive immune system has provided an excellent model for the study of higher-order chromatin structure and also provides a simple genetic system in which to dissect mechanisms of action for Hdac3. Lymphocytes rely on a series of recombinationdependent genome-editing processes, such as VDJ recombination and class-switch recombination, for their development and function. These recombination events are regulated through locus accessibility and require long-range chromatin interactions (17, 18). The Rag1 and Rag2 recombinases introduce DNA doublestrand breaks at recombination signal sequences, fol...

show abstract

“…Specifically, they propose that P-TEFb, which is inactivated by a complex containing HEXIM1 and the 7SK snRNP in untreated cells, is transiently released from this complex following HDAC or BET inhibition, thus enabling P-TEFb recruitment to and subsequent transcriptional induction of a defined set of alternative target genes 52. A more recent study demonstrated that HDACi treatment blocks transcriptional elongation and results in a re-distribution of BRD4 across the genome 68. Based on these findings, it is conceivable that BETi synergise with HDACi by targeting non-redundant regulatory mechanisms controlling transcriptional elongation of a specific subset of genes relevant for cancer progression.…”

Section: Translational Approaches To Tackle Epigenetic Dysregulation mentioning

confidence: 99%

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Heßmann¹,

Johnsen²,

Siveke

2016

Gut

103

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreatic cancer remains out of sight. Nevertheless, recent translational research activities propose that either modulation of the immune response or pharmacological targeting of epigenetic modifications alone, or in combination with chemotherapy, might open highly powerful therapeutic avenues in GI cancer entities, including pancreatic cancer. Deregulation of key epigenetic factors and chromatin-modifying proteins, particularly those responsible for the addition, removal or recognition of post-translational histone modifications, are frequently found in human pancreatic cancer and hence constitute particularly exciting treatment opportunities. This review summarises both current clinical trial activities and discovery programmes initiated throughout the biopharma landscape, and critically discusses the chances, hurdles and limitations of epigenetic-based therapy in future PDAC treatment.

show abstract

Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery

Cited by 146 publications

References 61 publications

An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian

An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Contact Info

Product

Resources

About