Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency

Tao Wang; Hao Wu; Yujing Li; Keith E. Szulwach; Li Lin; Xuekun Li; I. Ping Chen; Ian S. Goldlust; Stormy J. Chamberlain; Ann Dodd; He Gong; Gene Ananiev; Ji Woong Han; Young Sup Yoon; M. Katharine Rudd; Miao Yu; Chun Xiao Song; Chuan He; Qiang Chang; Stephen T. Warren; Peng Jin

doi:10.1038/ncb2748

Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency

Tao Wang, Hao Wu, Yujing Li, Keith E. Szulwach, Li Lin, Xuekun Li, I. Ping Chen, Ian S. Goldlust, Stormy J. Chamberlain, Ann Dodd, He Gong, Gene Ananiev, Ji Woong Han, Young Sup Yoon, M. Katharine Rudd, Miao Yu, Chun Xiao Song, Chuan He, Qiang Chang, Stephen T. WarrenPeng Jin

BioMedical Science Institute

Research output: Contribution to journal › Article › peer-review

82 Citations (Scopus)

Abstract

Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem cells (ESCs). Human ESCs (hESCs) contain 5-hydroxymethylcytosine (5hmC), which is generated through the oxidation of 5-methylcytosine by the TET enzyme family. Here we show that 5hmC levels increase significantly during reprogramming to human iPSCs mainly owing to TET1 activation, and this hydroxymethylation change is critical for optimal epigenetic reprogramming, but does not compromise primed pluripotency. Compared with hESCs, we find that iPSCs tend to form large-scale (100 kb-1.3 Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which exhibit incomplete hydroxymethylation on CG sites. Strikingly, these 5hmC aberrant hotspots largely coincide (∼ 80%) with aberrant iPSC-ESC non-CG methylation regions. Our results suggest that TET1-mediated 5hmC modification could contribute to the epigenetic variation of iPSCs and iPSC-hESC differences.

Original language	English
Pages (from-to)	700-711
Number of pages	12
Journal	Nature Cell Biology
Volume	15
Issue number	6
DOIs	https://doi.org/10.1038/ncb2748
Publication status	Published - 2013 Jun

Bibliographical note

Funding Information:
We thank J. Suhl, M. Santoro, S. Bray and C. Strauss for critical reading of the manuscript. We thank X. Huang from the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities for preparing the retrovirus/lentivirus used in this study. We are grateful to J. Mowrey, V. Patel, C. Street and S. Namburi for support on Illumina Hiseq2000/Miseq sequencing. This study was supported in part by the National Institutes of Health (NS079625 and HD073162 to P.J.; MH089606 and HD24064 to S.T.W.), the Emory Genetics Discovery Fund, and the Autism Speaks grant (#7660 to X.L.).

All Science Journal Classification (ASJC) codes

Cell Biology

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10.1038/ncb2748

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Wang, T., Wu, H., Li, Y., Szulwach, K. E., Lin, L., Li, X., Chen, I. P., Goldlust, I. S., Chamberlain, S. J., Dodd, A., Gong, H., Ananiev, G., Han, J. W., Yoon, Y. S., Katharine Rudd, M., Yu, M., Song, C. X., He, C., Chang, Q., ... Jin, P. (2013). Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency. Nature Cell Biology, 15(6), 700-711. https://doi.org/10.1038/ncb2748

@article{7f98c0196f484d35bf73d0f57e8c974a,

title = "Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency",

abstract = "Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem cells (ESCs). Human ESCs (hESCs) contain 5-hydroxymethylcytosine (5hmC), which is generated through the oxidation of 5-methylcytosine by the TET enzyme family. Here we show that 5hmC levels increase significantly during reprogramming to human iPSCs mainly owing to TET1 activation, and this hydroxymethylation change is critical for optimal epigenetic reprogramming, but does not compromise primed pluripotency. Compared with hESCs, we find that iPSCs tend to form large-scale (100 kb-1.3 Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which exhibit incomplete hydroxymethylation on CG sites. Strikingly, these 5hmC aberrant hotspots largely coincide (∼ 80%) with aberrant iPSC-ESC non-CG methylation regions. Our results suggest that TET1-mediated 5hmC modification could contribute to the epigenetic variation of iPSCs and iPSC-hESC differences.",

author = "Tao Wang and Hao Wu and Yujing Li and Szulwach, {Keith E.} and Li Lin and Xuekun Li and Chen, {I. Ping} and Goldlust, {Ian S.} and Chamberlain, {Stormy J.} and Ann Dodd and He Gong and Gene Ananiev and Han, {Ji Woong} and Yoon, {Young Sup} and {Katharine Rudd}, M. and Miao Yu and Song, {Chun Xiao} and Chuan He and Qiang Chang and Warren, {Stephen T.} and Peng Jin",

note = "Funding Information: We thank J. Suhl, M. Santoro, S. Bray and C. Strauss for critical reading of the manuscript. We thank X. Huang from the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities for preparing the retrovirus/lentivirus used in this study. We are grateful to J. Mowrey, V. Patel, C. Street and S. Namburi for support on Illumina Hiseq2000/Miseq sequencing. This study was supported in part by the National Institutes of Health (NS079625 and HD073162 to P.J.; MH089606 and HD24064 to S.T.W.), the Emory Genetics Discovery Fund, and the Autism Speaks grant (#7660 to X.L.).",

year = "2013",

month = jun,

doi = "10.1038/ncb2748",

language = "English",

volume = "15",

pages = "700--711",

journal = "Nature Cell Biology",

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Wang, T, Wu, H, Li, Y, Szulwach, KE, Lin, L, Li, X, Chen, IP, Goldlust, IS, Chamberlain, SJ, Dodd, A, Gong, H, Ananiev, G, Han, JW, Yoon, YS, Katharine Rudd, M, Yu, M, Song, CX, He, C, Chang, Q, Warren, ST & Jin, P 2013, 'Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency', Nature Cell Biology, vol. 15, no. 6, pp. 700-711. https://doi.org/10.1038/ncb2748

TY - JOUR

T1 - Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency

AU - Wang, Tao

AU - Wu, Hao

AU - Li, Yujing

AU - Szulwach, Keith E.

AU - Lin, Li

AU - Li, Xuekun

AU - Chen, I. Ping

AU - Goldlust, Ian S.

AU - Chamberlain, Stormy J.

AU - Dodd, Ann

AU - Gong, He

AU - Ananiev, Gene

AU - Han, Ji Woong

AU - Yoon, Young Sup

AU - Katharine Rudd, M.

AU - Yu, Miao

AU - Song, Chun Xiao

AU - He, Chuan

AU - Chang, Qiang

AU - Warren, Stephen T.

AU - Jin, Peng

N1 - Funding Information: We thank J. Suhl, M. Santoro, S. Bray and C. Strauss for critical reading of the manuscript. We thank X. Huang from the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities for preparing the retrovirus/lentivirus used in this study. We are grateful to J. Mowrey, V. Patel, C. Street and S. Namburi for support on Illumina Hiseq2000/Miseq sequencing. This study was supported in part by the National Institutes of Health (NS079625 and HD073162 to P.J.; MH089606 and HD24064 to S.T.W.), the Emory Genetics Discovery Fund, and the Autism Speaks grant (#7660 to X.L.).

PY - 2013/6

Y1 - 2013/6

N2 - Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem cells (ESCs). Human ESCs (hESCs) contain 5-hydroxymethylcytosine (5hmC), which is generated through the oxidation of 5-methylcytosine by the TET enzyme family. Here we show that 5hmC levels increase significantly during reprogramming to human iPSCs mainly owing to TET1 activation, and this hydroxymethylation change is critical for optimal epigenetic reprogramming, but does not compromise primed pluripotency. Compared with hESCs, we find that iPSCs tend to form large-scale (100 kb-1.3 Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which exhibit incomplete hydroxymethylation on CG sites. Strikingly, these 5hmC aberrant hotspots largely coincide (∼ 80%) with aberrant iPSC-ESC non-CG methylation regions. Our results suggest that TET1-mediated 5hmC modification could contribute to the epigenetic variation of iPSCs and iPSC-hESC differences.

AB - Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem cells (ESCs). Human ESCs (hESCs) contain 5-hydroxymethylcytosine (5hmC), which is generated through the oxidation of 5-methylcytosine by the TET enzyme family. Here we show that 5hmC levels increase significantly during reprogramming to human iPSCs mainly owing to TET1 activation, and this hydroxymethylation change is critical for optimal epigenetic reprogramming, but does not compromise primed pluripotency. Compared with hESCs, we find that iPSCs tend to form large-scale (100 kb-1.3 Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which exhibit incomplete hydroxymethylation on CG sites. Strikingly, these 5hmC aberrant hotspots largely coincide (∼ 80%) with aberrant iPSC-ESC non-CG methylation regions. Our results suggest that TET1-mediated 5hmC modification could contribute to the epigenetic variation of iPSCs and iPSC-hESC differences.

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Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency

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