Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development
Authors: Kristen L Kroll
Bo Zhang
James E Huettner
Emily M A Lewis
Edouard G Stanley
Paul Gontarz
Kesavan Meganathan
Andrew G Elefanty
Shaopeng Liu
Journal: Proceedings of the National Academy of Sciences of the United States of America (2017)
Discipline: Multidisciplinary
Keywords: CHD2; NKX2-1; cortical interneurons; human embryonic stem cells; medial ganglionic eminence.
Affiliations: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110., Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia., Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110., Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110; .

Abstract:  Cortical interneurons (cINs) modulate excitatory neuronal activity by providing local inhibition. During fetal development, several cIN subtypes derive from the medial ganglionic eminence (MGE), a transient ventral telencephalic structure. While altered cIN development contributes to neurodevelopmental disorders, the inaccessibility of human fetal brain tissue during development has hampered efforts to define molecular networks controlling this process. Here, we modified protocols for directed differentiation of human embryonic stem cells, obtaining efficient, accelerated production of MGE-like progenitors and MGE-derived cIN subtypes with the expected electrophysiological properties. We defined transcriptome changes accompanying this process and integrated these data with direct transcriptional targets of NKX2-1, a transcription factor controlling MGE specification. This analysis defined NKX2-1-associated genes with enriched expression during MGE specification and cIN differentiation, including known and previously unreported transcription factor targets with likely roles in MGE specification, and other target classes regulating cIN migration and function. NKX2-1-associated peaks were enriched for consensus binding motifs for NKX2-1, LHX, and SOX transcription factors, suggesting roles in coregulating MGE gene expression. Among the NKX2-1 direct target genes with cIN-enriched expression was CHD2, which encodes a chromatin remodeling protein mutated to cause human epilepsies. Accordingly, CHD2 deficiency impaired cIN specification and altered later electrophysiological function, while CHD2 coassociated with NKX2-1 at cis-regulatory elements and was required for their transactivation by NKX2-1 in MGE-like progenitors. This analysis identified several aspects of gene-regulatory networks underlying human MGE specification and suggested mechanisms by which NKX2-1 acts with chromatin remodeling activities to regulate gene expression programs underlying cIN development. 

Retracted: No

PubPeer comments:
 The number of samples reported in Fig 8C legend (3) doesn t match what is deposited in the NIH SRA - with only 2 Chd2 immunoprecipitated samples being available. ![file] ![file] , 
 The work in 8C is not ChIP-seq but rather ChIP-qPCR analysis, so n=3 in the legend is only referring to the ChIP RT-qPCR for the 3 genes and two control amplicons shown in the figure. This is not related to any of the datasets deposited in GEO. The data deposited in the Gene expression omnibus is not CHD2 ChIP-seq either, but rather is RNA-seq under conditions of CHD2 knockdown. For this work, one of the three replicate sample sets generated did not pass quality assurance and so was not included in the RNA-seq analysis or deposited into GEO. ,