TY - JOUR
T1 - β-actin regulates a heterochromatin landscape essential for optimal induction of neuronal programs during direct reprograming
AU - Xie, Xin
AU - Jankauskas, Robertas
AU - Mazari, Aslam M.A.
AU - Drou, Nizar
AU - Percipalle, Piergiorgio
N1 - Funding Information:
The research was funded by grants from the Swedish Research Council (www.vr.se), Cancerfonden (www.cancerfonden.se) and New York University Abu Dhabi (nyuad.nyu.edu) to PP. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank the NYU Abu Dhabi Center for Genomics and Systems Biology and Core Technology Platform Resources, for technical help. We appreciate the computational platform provided by NYUAD HPC team.
Publisher Copyright:
© 2018 Xie et al. http://creativecommons.org/licenses/by/4.0/.
PY - 2018/12
Y1 - 2018/12
N2 - During neuronal development, β-actin serves an important role in growth cone mediated axon guidance. Consistent with this notion, in vivo ablation of the β-actin gene leads to abnormalities in the nervous system. However, whether β-actin is involved in the regulation of neuronal gene programs is not known. In this study, we directly reprogramed β-actin +/+ WT, β-actin +/- HET and β-actin -/- KO mouse embryonic fibroblast (MEFs) into chemically induced neurons (CiNeurons). Using RNA-seq analysis, we profiled the transcriptome changes among the CiNeurons. We discovered that induction of neuronal gene programs was impaired in KO CiNeurons in comparison to WT ones, whereas HET CiNeurons showed an intermediate levels of induction. ChIP-seq analysis of heterochromatin markers demonstrated that the impaired expression of neuronal gene programs correlated with the elevated H3K9 and H3K27 methylation levels at gene loci in β-actin deficient MEFs, which is linked to the loss of chromatin association of the BAF complex ATPase subunit Brg1. Together, our study shows that heterochromatin alteration in β-actin null MEFs impedes the induction of neuronal gene programs during direct reprograming. These findings are in line with the notion that H3K9Me3-based heterochromatin forms a major epigenetic barrier during cell fate change.
AB - During neuronal development, β-actin serves an important role in growth cone mediated axon guidance. Consistent with this notion, in vivo ablation of the β-actin gene leads to abnormalities in the nervous system. However, whether β-actin is involved in the regulation of neuronal gene programs is not known. In this study, we directly reprogramed β-actin +/+ WT, β-actin +/- HET and β-actin -/- KO mouse embryonic fibroblast (MEFs) into chemically induced neurons (CiNeurons). Using RNA-seq analysis, we profiled the transcriptome changes among the CiNeurons. We discovered that induction of neuronal gene programs was impaired in KO CiNeurons in comparison to WT ones, whereas HET CiNeurons showed an intermediate levels of induction. ChIP-seq analysis of heterochromatin markers demonstrated that the impaired expression of neuronal gene programs correlated with the elevated H3K9 and H3K27 methylation levels at gene loci in β-actin deficient MEFs, which is linked to the loss of chromatin association of the BAF complex ATPase subunit Brg1. Together, our study shows that heterochromatin alteration in β-actin null MEFs impedes the induction of neuronal gene programs during direct reprograming. These findings are in line with the notion that H3K9Me3-based heterochromatin forms a major epigenetic barrier during cell fate change.
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U2 - 10.1371/journal.pgen.1007846
DO - 10.1371/journal.pgen.1007846
M3 - Article
C2 - 30557298
AN - SCOPUS:85059282468
SN - 1553-7390
VL - 14
JO - PLoS genetics
JF - PLoS genetics
IS - 12
M1 - e1007846
ER -