TY - JOUR
T1 - Rinf Regulates Pluripotency Network Genes and Tet Enzymes in Embryonic Stem Cells
AU - Ravichandran, Mirunalini
AU - Lei, Run
AU - Tang, Qin
AU - Zhao, Yilin
AU - Lee, Joun
AU - Ma, Liyang
AU - Chrysanthou, Stephanie
AU - Lorton, Benjamin M.
AU - Cvekl, Ales
AU - Shechter, David
AU - Zheng, Deyou
AU - Dawlaty, Meelad M.
N1 - Funding Information:
We thank the Einstein Epigenomics and Histopathology cores for NextGen sequencing and sectioning tissues, respectively. We are grateful to H. Su, H. Belalcazar, and B. Cattau for help with gene targeting and cloning. We also thank M. Suzuki (Greally lab), Y. Zhu (Suh lab), and F. Soldner for helpful discussions. M.M.D. is supported by Sidney Kimmel Foundation, Leukemia Research Foundation, R01GM122839, R01HL148852, NYSDOH/NYSTEM contract C32589GG, and funds from Albert Einstein College of Medicine Stem Cell Institute and Genetics Department. R.L. and S.C. are supported by The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund NYSDOH Contract C30292GG. D.S. is supported by R01GM108646. A.C. is supported by NIH/NEI EY014237 and EY012200. M.R. and R.L. performed the experiments. Q.T. and Y.Z. performed the bioinformatic analyses under the supervision of D.Z. and A.C. J.L. L.M. and S.C. contributed to maintenance and differentiation of ESCs. B.M.L. and D.S. contributed to in vitro protein interaction studies. M.M.D. conceived, designed, and supervised the study and secured funding. M.M.D. wrote the manuscript with input from M.R. D.Z. and other authors. The authors declare no competing interests.
Funding Information:
We thank the Einstein Epigenomics and Histopathology cores for NextGen sequencing and sectioning tissues, respectively. We are grateful to H. Su, H. Belalcazar, and B. Cattau for help with gene targeting and cloning. We also thank M. Suzuki (Greally lab), Y. Zhu (Suh lab), and F. Soldner for helpful discussions. M.M.D. is supported by Sidney Kimmel Foundation , Leukemia Research Foundation , R01GM122839 , R01HL148852 , NYSDOH/NYSTEM contract C32589GG , and funds from Albert Einstein College of Medicine Stem Cell Institute and Genetics Department . R.L. and S.C. are supported by The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund NYSDOH Contract C30292GG . D.S. is supported by R01GM108646 . A.C. is supported by NIH/NEI EY014237 and EY012200 .
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/8/20
Y1 - 2019/8/20
N2 - The Retinoid inducible nuclear factor (Rinf), also known as CXXC5, is a nuclear protein, but its functions in the context of the chromatin are poorly defined. We find that in mouse embryonic stem cells (mESCs), Rinf binds to the chromatin and is enriched at promoters and enhancers of Tet1, Tet2, and pluripotency genes. The Rinf-bound regions show significant overlapping occupancy of pluripotency factors Nanog, Oct4, and Sox2, as well as Tet1 and Tet2. We found that Rinf forms a complex with Nanog, Oct4, Tet1, and Tet2 and facilitates their proper recruitment to regulatory regions of pluripotency and Tet genes in ESCs to positively regulate their transcription. Rinf deficiency in ESCs reduces expression of Rinf target genes, including several pluripotency factors and Tet enzymes, and causes aberrant differentiation. Together, our findings establish Rinf as a regulator of the pluripotency network genes and Tet enzymes in ESCs.
AB - The Retinoid inducible nuclear factor (Rinf), also known as CXXC5, is a nuclear protein, but its functions in the context of the chromatin are poorly defined. We find that in mouse embryonic stem cells (mESCs), Rinf binds to the chromatin and is enriched at promoters and enhancers of Tet1, Tet2, and pluripotency genes. The Rinf-bound regions show significant overlapping occupancy of pluripotency factors Nanog, Oct4, and Sox2, as well as Tet1 and Tet2. We found that Rinf forms a complex with Nanog, Oct4, Tet1, and Tet2 and facilitates their proper recruitment to regulatory regions of pluripotency and Tet genes in ESCs to positively regulate their transcription. Rinf deficiency in ESCs reduces expression of Rinf target genes, including several pluripotency factors and Tet enzymes, and causes aberrant differentiation. Together, our findings establish Rinf as a regulator of the pluripotency network genes and Tet enzymes in ESCs.
KW - CXXC5
KW - ESC
KW - Nanog
KW - Rinf
KW - Tet enzymes
KW - pluripotency
UR - http://www.scopus.com/inward/record.url?scp=85070504427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070504427&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.07.080
DO - 10.1016/j.celrep.2019.07.080
M3 - Article
C2 - 31433977
AN - SCOPUS:85070504427
SN - 2211-1247
VL - 28
SP - 1993-2003.e5
JO - Cell Reports
JF - Cell Reports
IS - 8
ER -