Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

Justin Brumbaugh; Bruno Di Stefano; Xiuye Wang; Marti Borkent; Elmira Forouzmand; Katie J. Clowers; Fei Ji; Benjamin A. Schwarz; Marian Kalocsay; Stephen J. Elledge; Yue Chen; Ruslan I. Sadreyev; Steven P. Gygi; Guang Hu; Yongsheng Shi; Konrad Hochedlinger

doi:10.1016/j.cell.2017.11.023

Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

Justin Brumbaugh, Bruno Di Stefano, Xiuye Wang, Marti Borkent, Elmira Forouzmand, Katie J. Clowers, Fei Ji, Benjamin A. Schwarz, Marian Kalocsay, Stephen J. Elledge, Yue Chen, Ruslan I. Sadreyev, Steven P. Gygi, Guang Hu, Yongsheng Shi, Konrad Hochedlinger

Center for Mass Spectrometry and Proteomics

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

84 Scopus citations

Abstract

Cell fate transitions involve rapid gene expression changes and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we identified the RNA-processing factor Nudt21 as a novel regulator of cell fate change using transcription-factor-induced reprogramming as a screening assay. Suppression of Nudt21 enhanced the generation of induced pluripotent stem cells, facilitated transdifferentiation into trophoblast stem cells, and impaired differentiation of myeloid precursors and embryonic stem cells, suggesting a broader role for Nudt21 in cell fate change. We show that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency, although only a fraction changed protein levels. Remarkably, these proteins were strongly enriched for chromatin regulators, and their suppression neutralized the effect of Nudt21 during reprogramming. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling. Alternative polyadenylation exerts post-transcriptional control over cell fate decisions and pluripotency.

Original language	English (US)
Pages (from-to)	106-120.e21
Journal	Cell
Volume	172
Issue number	1-2
DOIs	https://doi.org/10.1016/j.cell.2017.11.023
State	Published - Jan 11 2018

Bibliographical note

Funding Information:
We thank Maris Handley, Amy Galvin, Marianne Gesner, and Eric Surette of the Harvard Stem Cell Institute flow cytometry core. We are grateful to David Sykes for sharing HOXB8-ER/LYZ-GFP cells. We thank Aaron Goldstrohm and members of the Hochedlinger lab for discussions. K.H. was supported by funds from the MGH , NIH ( R01 HD058013-06 , P01GM099134-06 ), and the Gerald and Darlene Jordan Chair in Regenerative Medicine . J.B. is grateful for support from the NIH ( 1F32HD078029-01A1 ). B.D.S. was supported by an EMBO long-term fellowship ( ALTF 1143-2015 ). Y.S. was supported by NIH grants GM090056 and CA17488 . G.H. was supported by the NIH Intramural Research Program ( Z01ES102745 ). S.J.E. was supported by the NIH ( AG11085 ).

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

Alternative polyadenylation
chromatin
embryonic stem cells
epigenetic regulation
induced pluripotent stem cells
induced trophoblast stem cells
microRNA
pluripotency
reprogramming
transdifferentiation

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Brumbaugh, J., Di Stefano, B., Wang, X., Borkent, M., Forouzmand, E., Clowers, K. J., Ji, F., Schwarz, B. A., Kalocsay, M., Elledge, S. J., Chen, Y., Sadreyev, R. I., Gygi, S. P., Hu, G., Shi, Y., & Hochedlinger, K. (2018). Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling. Cell, 172(1-2), 106-120.e21. https://doi.org/10.1016/j.cell.2017.11.023

Brumbaugh, J, Di Stefano, B, Wang, X, Borkent, M, Forouzmand, E, Clowers, KJ, Ji, F, Schwarz, BA, Kalocsay, M, Elledge, SJ, Chen, Y, Sadreyev, RI, Gygi, SP, Hu, G, Shi, Y & Hochedlinger, K 2018, 'Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling', Cell, vol. 172, no. 1-2, pp. 106-120.e21. https://doi.org/10.1016/j.cell.2017.11.023

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abstract = "Cell fate transitions involve rapid gene expression changes and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we identified the RNA-processing factor Nudt21 as a novel regulator of cell fate change using transcription-factor-induced reprogramming as a screening assay. Suppression of Nudt21 enhanced the generation of induced pluripotent stem cells, facilitated transdifferentiation into trophoblast stem cells, and impaired differentiation of myeloid precursors and embryonic stem cells, suggesting a broader role for Nudt21 in cell fate change. We show that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency, although only a fraction changed protein levels. Remarkably, these proteins were strongly enriched for chromatin regulators, and their suppression neutralized the effect of Nudt21 during reprogramming. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling. Alternative polyadenylation exerts post-transcriptional control over cell fate decisions and pluripotency.",

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author = "Justin Brumbaugh and {Di Stefano}, Bruno and Xiuye Wang and Marti Borkent and Elmira Forouzmand and Clowers, {Katie J.} and Fei Ji and Schwarz, {Benjamin A.} and Marian Kalocsay and Elledge, {Stephen J.} and Yue Chen and Sadreyev, {Ruslan I.} and Gygi, {Steven P.} and Guang Hu and Yongsheng Shi and Konrad Hochedlinger",

note = "Funding Information: We thank Maris Handley, Amy Galvin, Marianne Gesner, and Eric Surette of the Harvard Stem Cell Institute flow cytometry core. We are grateful to David Sykes for sharing HOXB8-ER/LYZ-GFP cells. We thank Aaron Goldstrohm and members of the Hochedlinger lab for discussions. K.H. was supported by funds from the MGH , NIH ( R01 HD058013-06 , P01GM099134-06 ), and the Gerald and Darlene Jordan Chair in Regenerative Medicine . J.B. is grateful for support from the NIH ( 1F32HD078029-01A1 ). B.D.S. was supported by an EMBO long-term fellowship ( ALTF 1143-2015 ). Y.S. was supported by NIH grants GM090056 and CA17488 . G.H. was supported by the NIH Intramural Research Program ( Z01ES102745 ). S.J.E. was supported by the NIH ( AG11085 ). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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AU - Forouzmand, Elmira

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AU - Ji, Fei

AU - Schwarz, Benjamin A.

AU - Kalocsay, Marian

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AU - Shi, Yongsheng

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N1 - Funding Information: We thank Maris Handley, Amy Galvin, Marianne Gesner, and Eric Surette of the Harvard Stem Cell Institute flow cytometry core. We are grateful to David Sykes for sharing HOXB8-ER/LYZ-GFP cells. We thank Aaron Goldstrohm and members of the Hochedlinger lab for discussions. K.H. was supported by funds from the MGH , NIH ( R01 HD058013-06 , P01GM099134-06 ), and the Gerald and Darlene Jordan Chair in Regenerative Medicine . J.B. is grateful for support from the NIH ( 1F32HD078029-01A1 ). B.D.S. was supported by an EMBO long-term fellowship ( ALTF 1143-2015 ). Y.S. was supported by NIH grants GM090056 and CA17488 . G.H. was supported by the NIH Intramural Research Program ( Z01ES102745 ). S.J.E. was supported by the NIH ( AG11085 ). Publisher Copyright: © 2017 Elsevier Inc.

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N2 - Cell fate transitions involve rapid gene expression changes and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we identified the RNA-processing factor Nudt21 as a novel regulator of cell fate change using transcription-factor-induced reprogramming as a screening assay. Suppression of Nudt21 enhanced the generation of induced pluripotent stem cells, facilitated transdifferentiation into trophoblast stem cells, and impaired differentiation of myeloid precursors and embryonic stem cells, suggesting a broader role for Nudt21 in cell fate change. We show that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency, although only a fraction changed protein levels. Remarkably, these proteins were strongly enriched for chromatin regulators, and their suppression neutralized the effect of Nudt21 during reprogramming. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling. Alternative polyadenylation exerts post-transcriptional control over cell fate decisions and pluripotency.

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Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

Abstract

Bibliographical note

Keywords

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