Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells

Abstract

Histone deacetylases 1 and 2 (HDAC1/2) form the core catalytic components of corepressor complexes that modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an ES cell line in which Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 resulted in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is dependent upon cell cycle progression, because differentiated, nonproliferating cells retain their viability. Furthermore, we observe increased mitotic defects, chromatin bridges, and micronuclei, suggesting HDAC1/2 are necessary for accurate chromosome segregation. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2-deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog, Esrrb, and Rex1. HDAC1/2 activity is regulated through binding of an inositol tetraphosphate molecule (IP 4 ) sandwiched between the HDAC and its cognate corepressor. This raises the important question of whether IP 4 regulates the activity of the complex in cells. By rescuing the viability of double-knockout cells, we demonstrate for the first time (to our knowledge) that mutations that abolish IP 4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors.

FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity

“…ChIP-qPCR at the same six ESC and six EpiC enhancers done for BRG1 validated these results and extended them to HDAC2, which is commonly found in a complex with HDAC1 (Lai and Wade, 2011;Jamaladdin et al, 2014) (Figures S5D and S5E). Consistent with a role for FOXD3 in recruiting as well as maintaining HDAC1 at the FOXD3-bound enhancer sites, HDAC1 was not found at the EpiC enhancers prior to FOXD3 binding (compare Figure 6K to 6L).…”

“…IP of FOXD3 showed that FOXD3 protein interacts with HDAC1/2, but not HDAC3, in both ESCs and EpiCs cells ( Figure 6G). As was the case with Brg1, evaluation of published expression data for HDAC1/2 double KO ESCs showed significant overlap in expression changes with Foxd3 KO cells, which was further enriched when considering only genes neighboring the FOXD3 enhancers ( Figure 6H) (Jamaladdin et al, 2014).…”

Molecular, biological characterization and drug sensitivity of chidamide‑resistant non‑small cell lung cancer cells

“…HDAC1 overexpression has been reported to be positively associated with cell division, differentiation and tumorigenesis (28)(29)(30). Loss of HDAC1 resulted in a 60% reduction in total HDAC activity and a loss of stem cell viability (28). Consistently, total HDAC activity was also elevated in A549-CHI-R and A549 HDAC1-overexpressed cells.…”

“…HDAC1 belongs to class I HDACs, which are the most closely associated with malignant phenotypes (27). HDAC1 overexpression has been reported to be positively associated with cell division, differentiation and tumorigenesis (28)(29)(30). Loss of HDAC1 resulted in a 60% reduction in total HDAC activity and a loss of stem cell viability (28).…”

Epigenetic regulation of ganglioside expression in neural stem cells and neuronal cells

“…Intriguingly, recent studies have suggested that glycans can contribute to epigenetic gene regulation as modulators. For example, a Bcarbohydrate-like^ molecule, inositol tetraphosphate (IP4; inositol 1, 3, 4, 5– tetrakisphosphate) acts as a stimulator to the activity of class I HDACs (HDAC1/2/3) [16–18]. Additionally, OGlcNAcylation has been reported to regulate localization, activity, and stability of many transcription factors, as well as their interactions with other proteins and DNA [19, 20].…”