Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Abstract

Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one of its least studied members. Here, we discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. We show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS-mutation affects CHD6 protein folding and impairs its ability to recruit co-factors in response to DNA damage or autophagy stimulation. This leads to an accumulation of DNA damage burden and to senescence-like phenotypes. By combining genomics and functional assays, we describe for the first time a molecular mechanism for the chromatin control of autophagic flux and genotoxic stress surveillance that applies broadly to human cell types and explains HSS onset.

Aging-associated changes in transcriptional elongation influence metazoan longevity

“…The RpII215 C4 fly strain (RRID:BDSC_3663), which carries a single point mutation (R741H) in the gene encoding the Drosophila RNA polymerase II 215kD subunit (RBP1), was received from the Bloomington Drosophila Stock Center (Bloomington, Indiana, USA). Flies carrying the RpII215 C4 allele (62) are homozygous viable but show a reduced transcription elongation rate (19). RpII215 C4 mutants were backcrossed for 6 generations into the outbred white Dahomey (wDah) wild type strain.…”

Role of ATP-dependent chromatin remodelers in hematopoietic stem and progenitor cell maintenance

“…Although the four members of this subfamily share constituent domains, they are distinct in chromatin remodeling specificities and enzyme activities [39]. CHD6 is a key regulator of DNA damage response, loss of which leads to impaired cell survival due to chronic oxidative stress, abnormal chromatin relaxation, amplified DNA damage signaling and checkpoint hypersensitivity [40,41]. The role of CHD6 in hematopoiesis and HSPC function is undetermined.…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…The third subfamily consists of the remaining family members CHD6-9 [ 219 ]. CHD6 mutations have previously been described, including a large translocation in one Pitt-Hopkins patient [ 220 ], in a single case of mental retardation [ 221 ], in sporadic acute myeloid leukaemia incidences [ 222 ], and most recently for the very rare Hallermann–Streiff syndrome [ 223 ]. CHD6 is the least studied member of the CHD family, and little is known for its contribution during neurodevelopment.…”