Social isolation stress induces ATF-7 phosphorylation and impairs silencing of the 5-HT 5B receptor gene.
Many symptoms induced by isolation rearing of rodents may be relevant to neuropsychiatric disorders, including depression. However, identities of transcription factors that regulate gene expression in response to chronic social isolation stress remain elusive. The transcription factor ATF-7 is structurally related to ATF-2, which is activated by various stresses, including inflammatory cytokines. Here, we report that Atf-7-deficient mice exhibit abnormal behaviours and increased 5-HT receptor 5B (Htr5b) mRNA levels in the dorsal raphe nuclei. ATF-7 silences the transcription of Htr5B by directly binding to its 5'-regulatory region, and mediates histone H3-K9 trimethylation via interaction with the ESET histone methyltransferase. Isolation-reared wild-type (WT) mice exhibit abnormal behaviours that resemble those of Atf-7-deficient mice. Upon social isolation stress, ATF-7 in the dorsal raphe nucleus is phosphorylated via p38 and is released from the Htr5b promoter, leading to the upregulation of Htr5b. Thus, ATF-7 may have a critical role in gene expression induced by social isolation stress.
Maekawa
Toshio
T
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, Tsukuba, Ibaraki, Japan. maekawa@rtc.riken.jp
Kim
Seungjoon
S
Nakai
Daisuke
D
Makino
Chieko
C
Takagi
Tsuyoshi
T
Ogura
Hiroo
H
Yamada
Kazuyuki
K
Chatton
Bruno
B
Ishii
Shunsuke
S
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D051696:Activating Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D015870:Gene Expression; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics*; D012919:Social Behavior; D012934:Social Isolation; D013315:Stress, Psychological
D051698:Activating Transcription Factor 2; D051696:Activating Transcription Factors; C497106:Atf2 protein, mouse; D006657:Histones; D012333:RNA, Messenger; D011985:Receptors, Serotonin; C078730:serotonin 5 receptor