The TFAP2C-Regulated OCT4 Naive Enhancer Is Involved in Human Germline Formation

Di Chen; Wanlu Liu; Jill Zimmerman; William A Pastor; Rachel Kim; Linzi Hosohama; Jamie Ho; Marianna Aslanyan; Joanna J Gell; Steven E Jacobsen; Amander T Clark

doi:10.1016/j.celrep.2018.12.011

The TFAP2C-Regulated OCT4 Naive Enhancer Is Involved in Human Germline Formation

Cell Rep. 2018 Dec 26;25(13):3591-3602.e5. doi: 10.1016/j.celrep.2018.12.011.

Authors

Affiliations

¹ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
² Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
³ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Pediatrics, Division of Hematology-Oncology, Los Angeles, CA 90095, USA; David Geffen School of Medicine, Los Angeles, CA 90095, USA.
⁵ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: clarka@ucla.edu.

Abstract

Human primordial germ cells (hPGCs) are the first embryonic progenitors in the germ cell lineage, yet the molecular mechanisms required for hPGC formation are not well characterized. To identify regulatory regions in hPGC development, we used the assay for transposase-accessible chromatin using sequencing (ATAC-seq) to systematically characterize regions of open chromatin in hPGCs and hPGC-like cells (hPGCLCs) differentiated from human embryonic stem cells (hESCs). We discovered regions of open chromatin unique to hPGCs and hPGCLCs that significantly overlap with TFAP2C-bound enhancers identified in the naive ground state of pluripotency. Using CRISPR/Cas9, we show that deleting the TFAP2C-bound naive enhancer at the OCT4 locus (also called POU5F1) results in impaired OCT4 expression and a negative effect on hPGCLC identity.

Keywords: OCT4; PGC; PGCLC; TFAP2C; enhancer; naive; pluripotency.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Chromatin / metabolism
Enhancer Elements, Genetic / genetics*
Female
Gene Expression Regulation, Developmental*
Germ Cells / cytology
Germ Cells / metabolism*
Humans
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / metabolism
Male
Nucleotide Motifs / genetics
Octamer Transcription Factor-3 / genetics*
Pluripotent Stem Cells / metabolism
Transcription Factor AP-2 / metabolism*
Transcriptome / genetics

Substances

Chromatin
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
Octamer Transcription Factor-3
POU5F1 protein, human
TFAP2C protein, human
Transcription Factor AP-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding