CHD7 in Charge of Neurogenesis

Progressive compaction of DNA wrapped around histone octamers  to  form  nucle-  osomes   and    higher-order   chromatin structures  constitutes an  organizational mechanism for  DNA storage.  However, this  compaction  also  presents  barriers to  gene  expression because  the  trans- criptional  machinery requires  access to DNA. Consequently, dynamic modulation of DNA accessibility by chromatin remod- eling  complexes is  an  important  mech- anism    for   controlling   cell   fate   during development  and,   when    deregulated, causing   disease.  In  this   issue   of  Cell Stem  Cell, Feng et al. (2013) seek to char-  acterize the  contributions  of  CHD7,  an ATP-dependent chromatin remodeler, to developmental and  adult neurogenesis.

Chromatin modifiers  can  be organized into  two  classes that  contribute to  tran- scriptional  regulation, those  that   cova- lently   modify   histones  and   those   that utilize   the   energy    of   ATP   hydrolysis  to  mobilize  nucleosomes  and   remodel chromatin structure.  Mutations in  genes encoding   chromatin    remodelers   are increasingly    recognized   as    frequently occurring in cancer (Wilson and  Rob- erts,   2011),   but   they   are   also   linked with  developmental  disorders. Some of these  include  ERCC6  in cerebro-oculo- facio-skeletal syndrome, ATRX in ATRX- syndrome  and    a-thalassemia   myelo- dyspasia    syndrome,   genes   encoding subunits  of  the   SWI/SNF   (BAF)   chro-  matin   remodeling  complex   in   Coffin- Siris             syndrome      (Tsurusaki     et       al.,

2012),   and    CHD7   in   CHARGE    syn- drome    (Clapier    and    Cairns,    2009). The CHD (chromodomain-helicase-DNA- binding  protein)  family is  a  subclass of ATP-dependent remodelers. De novo het- erozygous  mutations  of  CHD7  are  the

principal  cause of the  complex develop- mental    disorder    CHARGE   syndrome, characterized, in addition to other anoma- lies,   by   olfactory   defects  and   mental retardation (Bergman et al., 2011). Homo- zygous inactivation of Chd7  in  mice  re- sults in embryonic  lethality at  day  E10.5 while   heterozygous mutations produce phenotypes similar  to  human  CHARGE, including  postnatal growth  delay,  vestib- ular  dysfunction,  and   olfactory  defects (Bosman et al., 2005;  Hurd et al., 2007). However, the mechanisms by which mu- tation  of this  chromatin remodeler result in  specific  developmental   defects   are poorly understood.

In  this  issue   of  Cell  Stem   Cell,  Feng et   al.   (2013)   investigate   how   CHD7 contributes to  regulation  of  adult   neu- rogenesis.  They   show   that   CHD7  ex- pression   is    highly    enriched   in    the subventricular    zone    and    subgranular zone   (SVZ  and   SGZ),  two   neurogenic areas  of   the   mammalian  brain.   They demonstrate   that    CHD7    expression, although    not     present     in    quiescent neural  stem cells  (NSCs),  increases in active  NSCs,  peaks in  transit-amplifying progenitors,  and  persist in neuroblasts. The authors next  inactivate Chd7  in Tlx- or  Nestin-expressing  neural  stem cells (NSCs) using  Chd7 conditional mice  and find   that   deletion    of   CHD7   leads  to decrease of both  SVZ and  hippocampal neurogenesis. Loss of CHD7 is shown to have   no  effect upon   NSC  self-renewal but  instead  blocks  differentiation,  thus inhibiting   neurogenesis.   Consequently, CHD7 is dispensable for the maintenance of   NSC   populations,  but   essential   for differentiation  into   neural   populations. Notably,  the  authors  find  that  voluntary running is able to rescue the reduced hip-

pocampal   neurogenesis  of   the   CHD7 mutant mice.

To investigate the mechanistic basis for the contributions of CHD7 to NSC differ- entiation, the authors searched for genes whose  expression most  parallels that  of CHD7  itself,  reasoning that  such  genes may be enriched for direct targets of this chromatin  remodeler. Using  The  Cancer Genome Atlas (TCGA), two  transcription factors  essential   for   neuronal  identity, Sox4 and Sox11, were identified  as most highly correlated with CHD7  expression. The promoters of these genes were  then identified as bound by CHD7. The authors also show  that these genes are activated via CHD7 contributions to decompaction of  nucleosomes   at   their   promoters.  A central  role for Sox4  and  Sox11  is sug- gested by the finding that forced expres- sion   of   these  genes   circumvents  the differentiation   blockade  resulting    from CHD7 loss.

Collectively,   the  work  of  Feng   et  al. identify CHD7 as a regulator of neurogen- esis  that  directly controls the  acquisition of neural fate by regulating expression of transcription factors Sox4  and   Sox11 (Figure 1). Given that chromatin remodel- ing factors are typically capable of inter- acting   with  many  regulatory proteins (Batsukh et al., 2010), it will be of interest to  determine how  CHD7  is  targeted to Sox4  and  Sox11 promoters and  whether it  contributes to  other  aspects  of  chro-  matin structure at these targets.

Perhaps one  of the  most  provocative findings by Feng et al. is the amelioration of  the   CHD7   loss   phenotype  brought about   by   physical    exercise.   Exercise has   been  shown  to   have   stimulatory effects  upon   neurotransmitters  and   to increase  survival  of  nascent neurons in

 

Figure 1.  CHD7 and Physical Exercise in CHARGE Syndrome

CHD7 functions as  a  regulator of neurogenesis via direct  binding  to  the  promoters of fate-controlling transcription factors to facilitate open chromatin structure. Feng et al. show that exercise may ameliorate the neurogenic defects otherwise caused by CHD7 mutation.

modifiers    and   transcription   factors  to regulate transcription.  Gaining  a  deeper understanding   of  the   molecular  func- tion   of   CHD7   should    provide    insight into  CHARGE  syndrome, and  perhaps other    chromatin-based   diseases,  and may  offer clues  for  novel  approaches to therapy.