Gene expression regulation by the Chromodomain helicase DNA-binding protein 9 (CHD9) chromatin remodeler is dispensable for murine development

Abstract

Chromodomain helicase DNA-binding (CHD) chromatin remodelers regulate transcription and DNA repair. They govern cell-fate decisions during embryonic development and are often deregulated in human pathologies. Chd1-8 show upon germline disruption pronounced, often developmental lethal phenotypes. Here we show that contrary to Chd1-8 disruption, Chd9 -/animals are viable, fertile and display no developmental defects or disease predisposition. Germline deletion of Chd9 only moderately affects gene expression in tissues and derived cells, whereas acute depletion in human cancer cells elicits more robust changes suggesting that CHD9 is a highly context-dependent chromatin regulator that, surprisingly, is dispensable for mouse development.

CHD2-Related CNS Pathologies

“…A variant form of CHD9 that localizes in the nucleolus and associates with RNA polymerase I (RNAPI) has recently been identified [ 61 ]. Further, it has been demonstrated that Chd9 −/− (knockout) mice are viable and develop normally [ 62 ], given the incidence of CHD9 dysregulation in many cancers this finding supports a vital role in the DNA damage response. This also suggests that some of the CHD family proteins may offer some overlap in function and possibly compensation in cases of haploinsufficiency while others may have exceptionally unique functionality.…”

Sentinels of chromatin: chromodomain helicase DNA-binding proteins in development and disease

“…For instance, some, such as CHD1, are required for RNAPII transcription ( Krogan et al 2002 ; Simic 2003 ; Srinivasan et al 2005 ; Warner et al 2007 ; Skene et al 2014 ; Dieuleveult et al 2016 ; Baumgart et al 2017 ) and play a role in transcription initiation ( Lin et al 2011 ) and in RNAPII-directed turnover of promoter-proximal nucleosomes, promoter escape, and subsequent elongation and splicing ( Sims et al 2007 ; Skene et al 2014 ). Similarly, mounting evidence shows that mammalian CHD2 ( Rom et al 2019 ), CHD6 ( Lutz et al 2006 ), CHD8 ( Rodríguez-Paredes et al 2009 ; Ceballos-Chávez et al 2015 ), and CHD9 ( Shur et al 2006a ; Lee and Stallcup 2017 ; Alendar et al 2020 ; Newton and Pask 2020 ; Yoo et al 2020 ) potentiate transcription of distinct target genes in diverse cell types. CHD enzymes also contribute to transcriptional repression, best exemplified by the concerted action of chromatin remodeling and histone deacetylase catalytic subunits of the NuRD complex, which generally leads to the generation of hypoacetylated, densely packed chromatin ( Lai and Wade 2011 ) and facilitates PRC2-mediated silencing of target genes in ESCs ( Reynolds et al 2012 ).…”

Genetic Variability of the Functional Domains of Chromodomains Helicase DNA-Binding (CHD) Proteins

“…CHD9 also shows a high number of variable residues among orthologues (Figure 2B). Although CHD9 continues to be the less well-characterized member of the subfamily III [47], its role in the regulation of expression of osteogenic cells [69,70] has been well documented. In contrast, a recent study revealed that mice with depleted CHD9 survived and were fertile, indicating that CHD9 is dispensable for murine embryonic development [47].…”

“…Although CHD9 continues to be the less well-characterized member of the subfamily III [47], its role in the regulation of expression of osteogenic cells [69,70] has been well documented. In contrast, a recent study revealed that mice with depleted CHD9 survived and were fertile, indicating that CHD9 is dispensable for murine embryonic development [47]. The same study demonstrated that acute depletion of CHD9 in human cancer cells elicited more robust gene expression changes, suggesting that CHD9 is a highly context-dependent chromatin regulator.…”

“…Lin and colleagues [43] reported several differences between mice and human transcriptional landscapes, partially explained by the metabolic and physiological differences among the species. If murine CHDs have been the focus of most studies performed until now [2,3,16,17,[19][20][21][44][45][46][47], the near prospects are to extend the strategy to other non-human mammals because they are assumed to be the most suitable models for brain research. Evolutionary constraints are crucial for understanding the history of these proteins and to predict the impact that new mutations will eventually have on the protein.…”