Transcriptomic Profiling and H3K27me3 Distribution Reveal Both Demethylase-Dependent and Independent Regulation of Developmental Gene Transcription in Cell Differentiation

TY - JOUR

T1 - Transcriptomic Profiling and H3K27me3 Distribution Reveal Both Demethylase-Dependent and Independent Regulation of Developmental Gene Transcription in Cell Differentiation

AU - Kang, Sung Chul

AU - Kim, Se Kye

AU - Chai, Jin Choul

AU - Kim, Sun Hwa

AU - Won, Kyoung-Jae

AU - Lee, Young Seek

AU - Jung, Kyoung Hwa

AU - Chai, Young Gyu

PY - 2015/8/11

Y1 - 2015/8/11

N2 - 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.

AB - 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.

KW - Benzazepines/pharmacology

KW - Cell Differentiation/drug effects

KW - Cell Line, Tumor

KW - DNA Methylation

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Developmental/drug effects

KW - Gene Knockout Techniques

KW - Histones/metabolism

KW - Humans

KW - Jumonji Domain-Containing Histone Demethylases/genetics

KW - Pyrimidines/pharmacology

KW - Reproducibility of Results

KW - Transcriptome

KW - Tretinoin/pharmacology

U2 - 10.1371/journal.pone.0135276

DO - 10.1371/journal.pone.0135276

M3 - Journal article

C2 - 26263556

SN - 1932-6203

VL - 10

SP - e0135276

JO - PLoS ONE

JF - PLoS ONE

IS - 8

ER -