TY - JOUR
T1 - CIC is a critical regulator of neuronal differentiation
AU - Hwang, Inah
AU - Pan, Heng
AU - Yao, Jun
AU - Elemento, Olivier
AU - Zheng, Hongwu
AU - Paik, Jihye
N1 - Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/5/7
Y1 - 2020/5/7
N2 - Capicua (CIC), a member of the high mobility group-box (HMG-box) superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. However, its functions in brain development and tumorigenesis remain poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblasts to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogate involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1- containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. Together, this study uncovers a potentially novel regulatory pathway of CIC-dependent neuronal differentiation and may implicate these molecular mechanisms in CIC-dependent brain tumorigenesis.
AB - Capicua (CIC), a member of the high mobility group-box (HMG-box) superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. However, its functions in brain development and tumorigenesis remain poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblasts to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogate involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1- containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. Together, this study uncovers a potentially novel regulatory pathway of CIC-dependent neuronal differentiation and may implicate these molecular mechanisms in CIC-dependent brain tumorigenesis.
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U2 - 10.1172/jci.insight.135826
DO - 10.1172/jci.insight.135826
M3 - Article
C2 - 32229723
AN - SCOPUS:85084380062
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 9
M1 - e135826
ER -