The chromatin remodeller CHD8 is required for E2F-dependent transcription activation of S-phase genes

Abstract

The precise regulation of S-phase–specific genes is critical for cell proliferation. How the repressive chromatin configuration mediated by the retinoblastoma protein and repressor E2F factors changes at the G1/S transition to allow transcription activation is unclear. Here we show ChIP-on-chip studies that reveal that the chromatin remodeller CHD8 binds ∼2000 transcriptionally active promoters. The spectrum of CHD8 target genes was enriched in E2F-dependent genes. We found that CHD8 binds E2F-dependent promoters at the G1/S transition but not in quiescent cells. Consistently, CHD8 was required for G1/S-specific expression of these genes and for cell cycle re-entry on serum stimulation of quiescent cells. We also show that CHD8 interacts with E2F1 and, importantly, loading of E2F1 and E2F3, but not E2F4, onto S-specific promoters, requires CHD8. However, CHD8 recruiting is independent of these factors. Recruiting of MLL histone methyltransferase complexes to S-specific promoters was also severely impaired in the absence of CHD8. Furthermore, depletion of CHD8 abolished E2F1 overexpression-dependent S-phase stimulation of serum-starved cells, highlighting the essential role of CHD8 in E2F-dependent transcription activation.

Amplification of the NSD3‑BRD4‑CHD8 pathway in pelvic high‑grade serous carcinomas of tubo‑ovarian and endometrial origin

“…In addition, based on our overall and progression-free survival curve analyses, prognosis appears to be better correlated with amplification rather than mRNA expression, suggesting a potential collaborative role of co-amplified genes in the amplicons. Despite being a part of amplicons, there are several studies demonstrating the importance of NSD3, CHD8 and BRD4 in oncological processes (27)(28)(29)(30)(31), and it is noteworthy that amplicons may not necessarily contain only one oncogene, but may act as a unit with several genes of importance (26). Future knockdown of NSD3, BRD4 and CHD8 or treatment of HGSC displaying pathway amplification with BRD4-specific small-molecule inhibitors are required to confirm the growth-promoting properties of specific gene amplification in patients with pelvic HGSC.…”

BioID identifies novel c-MYC interacting partners in cultured cells and xenograft tumors

“…Like MYC, CHD8 has also been linked to chromatin remodeling, transcriptional activation and repression. For example, CHD8 is involved in both the activation of androgen receptor and E2F1-regulated target genes [54,55], and in the repression of beta-catenin-and p53-dependent gene activation [56,57]. Future studies will be directed toward understanding the importance of the CHD8 interaction in MYC function.…”

Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation

“…1A). We also evaluated the activities of E2Fx4, which plays a critical role in the G1 → S phase transition activated by p-Rb [34], and found that these were reduced progressively in gemigliptin-treated VSMCs (Fig. 2C).…”