Transcriptomic Profiling and H3K27me3 Distribution Reveal Both Demethylase-Dependent and Independent Regulation of Developmental Gene Transcription in Cell Differentiation.
The removal of histone H3 trimethylation at lysine residue 27 (H3K27me3) plays a critical role in the transcriptional initiation of developmental genes. The H3K27me3-specific KDM6 demethylases JMJD3 and UTX are responsible for the transcriptional initiation of various developmental genes, but some genes are expressed in a KDM6 demethylase-independent manner. To address the role of H3K27me3 in the retinoic acid (RA)-induced differentiation of the human carcinoma NCCIT cell line, we inhibited JMJD3 and UTX using the H3K27me3 demethylase inhibitor GSK-J4. The commitment of JMJD3/UTX-inhibited cells to a specific fate was delayed, and transcriptome profiling also revealed the differential expression of genes related to cell fate specification in demethylase-inactivated cells; the expression levels of RA metabolism and HOX family genes significantly decreased. We observed a weak correlation between H3K27me3 enrichment and transcriptional repression in the control and JMJD/UTX-inhibited cells, except for a few sets of developmental genes that are indispensable for cell fate specification. Taken together, these results provide the H3K27me3 landscape of a differentiating cell line and suggest that both demethylase-dependent and demethylase-independent transcriptional regulation play a role in early differentiation and developmental gene expression activated by H3K27me3 demethylation.
Department of Nanobiotechnology, Hanyang University, Seoul, Republic of Korea.
Sung Chul
SC
Kang
Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea.
Se Kye
SK
Kim
Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea.
Jin Choul
JC
Chai
Department of Nanobiotechnology, Hanyang University, Seoul, Republic of Korea.
Sun Hwa
SH
Kim
Institute of Diabetes, Obesity, and Metabolism, Genetics Department, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States of America.
Kyoung-Jae
KJ
Won
Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea.
Young Seek
YS
Lee
Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea.
Kyoung Hwa
KH
Jung
Department of Nanobiotechnology, Hanyang University, Seoul, Republic of Korea; Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea.
Young Gyu
YG
Chai
D001552:Benzazepines / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055786:Gene Knockout Techniques; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D015203:Reproducibility of Results; D059467:Transcriptome; D014212:Tretinoin / Q000494:pharmacology
D001552:Benzazepines; C000593030:GSK-J4; D006657:Histones; D011743:Pyrimidines; D014212:Tretinoin; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human