Mutation of the SNF2 family member Chd2 affects mouse development and survival

Abstract

The chromodomain helicase DNA-binding domain (Chd) proteins belong to the SNF2-like family of ATPases that function in chromatin remodeling and assembly. These proteins are characterized by the presence of tandem chromodomains and are further subdivided based on the presence or absence of additional structural motifs. The Chd1-Chd2 subfamily is distinguished by the presence of a DNA-binding domain that recognizes AT-rich sequence. Currently, there are no reports addressing the function of the Chd2 family member. Embryonic stem cells containing a retroviral gene-trap inserted at the Chd2 locus were utilized to generate mice expressing a Chd2 protein lacking the DNA-binding domain. This mutation in Chd2 resulted in a general growth delay in homozygous mutants late in embryogenesis and in perinatal lethality. Animals heterozygous for the mutation showed decreased neonatal viability and increased susceptibility to non-neoplastic lesions affecting most primary organs. In particular, approximately 85% of the heterozygotes showed gross kidney abnormalities. Our results demonstrate that mutation of Chd2 dramatically affects mammalian development and long-term survival.

The Chd family of chromatin remodelers

“…Expression profiles for hCHD1 and hCHD2 have revealed global expression of these genes [10]. Mouse Chd2 mRNA is also ubiquitously expressed in adult tissues [47]. The absolute levels of mRNA expression in the different tissues analyzed were similar except for heart tissue, where Chd2 mRNA was highly expressed [47].…”

“…This mutation in Chd2 resulted in a general growth delay in homozygous mutants late in embryogenesis and in perinatal lethality [47]. Animals heterozygous for the mutation showed decreased neonatal viability and increased susceptibility to non-neoplastic lesions affecting most primary organs.…”

“…Animals heterozygous for the mutation showed decreased neonatal viability and increased susceptibility to non-neoplastic lesions affecting most primary organs. In particular, approximately 85% of the heterozygotes showed gross kidney abnormalities [47].…”

ATP-dependent chromatin remodeling during mammalian development

“…This NuRDmediated repression involves deacetylation of histone 3 at K9/14/27 and subsequent demethylation of H3K4me3 at the promoters of these genes. In contrast, CHD5, which is highly expressed in both fetal and adult brain, is required during neuronal differentiation to Gaspar-Maia et al, 2009;Guzman-Ayala et al, 2015;Piatti et al, 2015), post-implantation development (Suzuki et al, 2015) and during hematopoietic stem and progenitor cell formation ) CHD2 CHD2 Affects mouse survival as homozygous Chd2 mutants show perinatal lethality (Marfella et al, 2006), CHD2 influences chromatin accessibility and histone H3.3 deposition at active chromatin regions (Siggens et al, 2015) CHD3 or CHD4 (NuRD complex) CHD3 or CHD4, HDAC1, HDAC2, MBD3 or MBD2, MTA1 or MTA2/3, RBAP46 (Rbbp7), RBAP48 (Rbbp4)…”

A Novel Genetic Syndrome Caused by Haploinsufficiency of CHD2, a Regulator of Chromatin Structure

“…Mice homozygous for a C-terminal truncating mutation of CHD2 are not viable, with general growth delay in late embryogenesis and perinatal death [20]. Heterozygous Chd2 mutants exhibit decreased survival rates, especially in the neonatal period, and have increased incidence of non-neoplastic lesions affecting a number of primary organs, most notably the kidneys.…”