TY - JOUR
T1 - MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain
AU - Chen, Jiayang
AU - Fuhler, Nicole A.
AU - Noguchi, Kevin K.
AU - Dougherty, Joseph D.
N1 - Funding Information:
We thank Dr. Brian Clark, Dr. Harrison Gabel, Dr. Kristen Kroll, Colin Florian, Nicole Hamagami, and Diana Christian for technical assistance and scientific advice. We also thank Sneha Chaturvedi, Simona Sarafinovska, Dr. Anthony Fischer, and Dr. Michael Vasek for manuscript proofreading. Funding was provided by The Jakob Gene Fund, the Mallinckrodt Institute of Radiology at Washington University School of Medicine, McDonnell International Scholars Academy (J.C.), and the National Institutes of Health (NIH): R01MH107515, R01MH124808 to J.D.D., and NIH 5UL1TR002 345 (Institute of Clinical and Translational Sciences) and P50 HD103525 (Intellectual and Developmental Disabilities Research Center).
Publisher Copyright:
© 2023 Cold Spring Harbor Laboratory Press. All rights reserved.
PY - 2023/4
Y1 - 2023/4
N2 - In vitro studies indicate the neurodevelopmental disorder gene myelin transcription factor 1-like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L’s molecular and cellular functions in the adult mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) gene expression, corresponding to an increased ratio of DL/UL neurons in the adult mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets and epigenetic changes following MYT1L loss in mouse developing cortex and adult prefrontal cortex (PFC). We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multiomic data set integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but increases H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as Bcl11b, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we showed that MYT1L interacts with HDAC2 and transcriptional repressor SIN3B in vivo, providing potential mechanisms underlying repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights into how MYT1L loss leads to aberrant activation of earlier neuronal development programs in the adult mouse brain.
AB - In vitro studies indicate the neurodevelopmental disorder gene myelin transcription factor 1-like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L’s molecular and cellular functions in the adult mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) gene expression, corresponding to an increased ratio of DL/UL neurons in the adult mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets and epigenetic changes following MYT1L loss in mouse developing cortex and adult prefrontal cortex (PFC). We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multiomic data set integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but increases H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as Bcl11b, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we showed that MYT1L interacts with HDAC2 and transcriptional repressor SIN3B in vivo, providing potential mechanisms underlying repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights into how MYT1L loss leads to aberrant activation of earlier neuronal development programs in the adult mouse brain.
UR - http://www.scopus.com/inward/record.url?scp=85159735299&partnerID=8YFLogxK
U2 - 10.1101/gr.277413.122
DO - 10.1101/gr.277413.122
M3 - Article
C2 - 37100461
AN - SCOPUS:85159735299
SN - 1088-9051
VL - 33
SP - 541
EP - 556
JO - Genome research
JF - Genome research
IS - 4
ER -