Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.

TitleStress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.
Publication TypeJournal Article
Year of Publication2019
AuthorsLorsch ZS, Hamilton PJ, Ramakrishnan A, Parise EM, Salery M, Wright WJ, Lepack AE, Mews P, Issler O, McKenzie A, Zhou X, Parise LF, Pirpinias ST, Torres IOrtiz, Kronman HG, Montgomery SE, Loh Y-HEddie, Labonte B, Conkey A, Symonds AE, Neve RL, Turecki G, Maze I, Dong Y, Zhang B, Shen L, Bagot RC, Nestler EJ
JournalNat Neurosci
Volume22
Issue9
Pagination1413-1423
Date Published2019 Sep
ISSN1546-1726
Abstract

Understanding the transcriptional changes that are engaged in stress resilience may reveal novel antidepressant targets. Here we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB-Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in prefrontal cortex neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB-Zfp189 interactions in mediating a central transcriptional network of resilience.

DOI10.1038/s41593-019-0462-8
Alternate JournalNat. Neurosci.
PubMed ID31427770
PubMed Central IDPMC6713580
Grant ListP50MH096890 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
K99DA045795 / / U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) /
T32 GM007280 / GM / NIGMS NIH HHS / United States
T32MH096678 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
P01 DA047233 / DA / NIDA NIH HHS / United States
K99 DA045795 / DA / NIDA NIH HHS / United States
RF1 AG057440 / AG / NIA NIH HHS / United States
F30MH110073 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
R01MH051399 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
R01 MH051399 / MH / NIMH NIH HHS / United States
P50 MH096890 / MH / NIMH NIH HHS / United States
T32 MH096678 / MH / NIMH NIH HHS / United States
R01 AG057907 / AG / NIA NIH HHS / United States
U01 AG046170 / AG / NIA NIH HHS / United States
F30 MH110073 / MH / NIMH NIH HHS / United States