The nuclear factor CECR2 promotes somatic cell reprogramming by reorganizing the chromatin structure

Abstract

Somatic cells can be reprogrammed into pluripotent stem cells with a minimal set of defined factors, Oct3/4, Sox2, Klf4, and c-Myc, also known as OKSM, although this reprogramming is somewhat inefficient. Recent work has identified other nuclear factors, including SALL4, that can synergize with the OSK factors to improve reprogramming dynamics, but the specific role of each of these factors remains poorly understood. In this study, we sought to learn more about the role of SALL4. We observed that SALL4 was the most significant factor in promoting OKS-induced reprogramming. To look for molecules downstream of SALL4, we screened a set of putative targets to determine whether they could promote OKS-induced reprogramming. We identified CECR2, a multidomain nuclear factor and histone acetyl-lysine reader, as a SALL4 effector. Mechanistically, we determined that SALL4 activates Cecr2 expression by directly binding to its promotor region. CECR2 in turn promotes reprogramming by forming a chromatin remodeling complex; this complex contained the SWI/SNF family member SMARCA1 and was dependent on CECR2’s DTT domain. In combination, our findings suggest that CECR2 is a novel reprogramming factor and works through a protein network to overcome epigenetic barriers during reprogramming. Somatic cells can be reprogrammed into pluripotent stem cells with a minimal set of defined factors, Oct3/4, Sox2, Klf4, and c-Myc, also known as OKSM, although this reprogramming is somewhat inefficient. Recent work has identified other nuclear factors, including SALL4, that can synergize with the OSK factors to improve reprogramming dynamics, but the specific role of each of these factors remains poorly understood. In this study, we sought to learn more about the role of SALL4. We observed that SALL4 was the most significant factor in promoting OKS-induced reprogramming. To look for molecules downstream of SALL4, we screened a set of putative targets to determine whether they could promote OKS-induced reprogramming. We identified CECR2, a multidomain nuclear factor and histone acetyl-lysine reader, as a SALL4 effector. Mechanistically, we determined that SALL4 activates Cecr2 expression by directly binding to its promotor region. CECR2 in turn promotes reprogramming by forming a chromatin remodeling complex; this complex contained the SWI/SNF family member SMARCA1 and was dependent on CECR2’s DTT domain. In combination, our findings suggest that CECR2 is a novel reprogramming factor and works through a protein network to overcome epigenetic barriers during reprogramming. Somatic cells can be reprogramed into pluripotent stem cells by overexpression of a set of nuclear factors Oct4/Sox2/Klf4/c-Myc (OKSM) or Yamanaka factors (1Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (16937) Google Scholar) in mouse, or Oct4/Sox2/Nanog/Lin28 in human (2Yu J. Vodyanik M.A. Smuga-Otto K. Antosiewicz-Bourget J. Frane J.L. Tian S. Nie J. Jonsdottir G.A. Ruotti V. Stewart R. Slukvin I.I. Thomson J.A. Induced pluripotent stem cell lines derived from human somatic cells.Science. 2007; 318: 1917-1920Crossref PubMed Scopus (7574) Google Scholar), alternatively. This revolutionary technic, which was termed induced pluripotent stem cells (iPSCs), promised a great opportunity in regeneration medicine. Previously, the reprogramming by OKSM was low in efficiency and dynamics, and the use of oncogene c-Myc, raising the concern of tumorigenicity for the resulting iPSCs. Thus, the alteration of the reprogramming factors, especially the use of nononcogenes or other non-Yamanaka factors, will offer us a safer somatic cell reprogramming technique and new insight(s) for the underlying mechanism in somatic cell reprogramming. Indeed, a set of nuclear factors were reported to play roles in iPSC induction by replacing or combining with the Yamanaka factors. Generally, these nuclear factors can be categorized into two groups: (1) transcriptional factors, which can facilitate somatic cell reprogramming by binding to specific nuclear sequences or motifs, such as Glis1 (3Maekawa M. Yamaguchi K. Nakamura T. Shibukawa R. Kodanaka I. Ichisaka T. Kawamura Y. Mochizuki H. Goshima N. Yamanaka S. Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1.Nature. 2011; 474: 225-229Crossref PubMed Scopus (272) Google Scholar), Nr5a2 (4Heng J.C. Feng B. Han J. Jiang J. Kraus P. Ng J.H. Orlov Y.L. Huss M. Yang L. Lufkin T. Lim B. Ng H.H. The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells.Cell Stem Cell. 2010; 6: 167-174Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar), Sall4 (5Tsubooka N. Ichisaka T. Okita K. Takahashi K. Nakagawa M. Yamanaka S. Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts.Genes Cells. 2009; 14: 683-694Crossref PubMed Scopus (111) Google Scholar, 6Buganim Y. Markoulaki S. van Wietmarschen N. Hoke H. Wu T. Ganz K. Akhtar-Zaidi B. He Y. Abraham B.J. Porubsky D. Kulenkampff E. Faddah D.A. Shi L. Gao Q. Sarkar S. et al.The developmental potential of iPSCs is greatly influenced by reprogramming factor selection.Cell Stem Cell. 2014; 15: 295-309Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar), Esrrb (7Feng B. Jiang J. Kraus P. Ng J.H. Heng J.C. Chan Y.S. Yaw L.P. Zhang W. Loh Y.H. Han J. Vega V.B. Cacheux-Rataboul V. Lim B. Lufkin T. Ng H.H. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb.Nat. Cell Biol. 2009; 11: 197-203Crossref PubMed Scopus (355) Google Scholar), Dax1 (8Zhang J. Liu G. Ruan Y. Wang J. Zhao K. Wan Y. Liu B. Zheng H. Peng T. Wu W. He P. Hu F.Q. Jian R. Dax1 and Nanog act in parallel to stabilize mouse embryonic stem cells and induced pluripotency.Nat. Commun. 2014; 5: 5042Crossref PubMed Scopus (32) Google Scholar), Zscan4 (9Hirata T. Amano T. Nakatake Y. Amano M. Piao Y. Hoang H.G. Ko M.S. Zscan4 transiently reactivates early embryonic genes during the generation of induced pluripotent stem cells.Sci. Rep. 2012; 2: 208Crossref PubMed Scopus (61) Google Scholar), Tbx3 (10Han J. Yuan P. Yang H. Zhang J. Soh B.S. Li P. Lim S.L. Cao S. Tay J. Orlov Y.L. Lufkin T. Ng H.-H. Tam W.-L. Lim B. Tbx3 improves the germ-line competency of induced pluripotent stem cells.Nature. 2010; 463: 1096-1100Crossref PubMed Scopus (215) Google Scholar), and Prdm14 (11Habib O. Habib G. Moon S.H. Hong K.S. Do J.T. Choi Y. Chang S.W. Chung H.M. Ground-state conditions promote robust Prdm14 reactivation and maintain an active Dlk1-Dio3 region during reprogramming.Mol. Cells. 2014; 37: 31-35Crossref PubMed Scopus (3) Google Scholar); (2) epigenetic regulators, which facilitate somatic cell reprogramming by altering the chromatin structure or DNA/histone modifications, such as Tet1 (12Chen J. Guo L. Zhang L. Wu H. Yang J. Liu H. Wang X. Hu X. Gu T. Zhou Z. Liu J. Liu J. Wu H. Mao S.Q. Mo K. et al.Vitamin C modulates TET1 function during somatic cell reprogramming.Nat. Genet. 2013; 45: 1504-1509Crossref PubMed Scopus (204) Google Scholar, 13Gao Y. Chen J. Li K. Wu T. Huang B. Liu W. Kou X. Zhang Y. Huang H. Jiang Y. Yao C. Liu X. Lu Z. Xu Z. Kang L. et al.Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming.Cell Stem Cell. 2013; 12: 453-469Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar), Brg1 (14Singhal N. Graumann J. Wu G. Araúzo-Bravo M.J. Han D.W. Greber B. Gentile L. Mann M. Schöler H.R. Chromatin-remodeling components of the BAF complex facilitate reprogramming.Cell. 2010; 141: 943-955Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). Despite the discovery of a set of nuclear factors that facilitate reprogramming, the systematic comparison of their effects, especially in efficiency and dynamics, on reprogramming is lacking. A function ranking of these factors on reprogramming may help us to diagnose the key points of the underlying mechanisms systematically and comprehensively. Previously, we reported a combination of seven factors reprogramming cocktails (Nanog-Esrrb-Glis1-Jdp2-Kdm2b-Sall4-Mkk6) (15Wang B. Wu L. Li D. Liu Y. Guo J. Li C. Yao Y. Wang Y. Zhao G. Wang X. Fu M. Liu H. Cao S. Wu C. Yu S. et al.Induction of pluripotent stem cells from mouse embryonic fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-sall4.Cell Rep. 2019; 27: 3473-3485.e3475Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), in which the dropout of Sall4 led a max reduction in the reprogramming efficiency, suggesting an outstanding role for Sall4 in cell fate determination. Consistently, Sall4 is reported to play an important role in a range of biological processes, such as somatic cell reprograming (5Tsubooka N. Ichisaka T. Okita K. Takahashi K. Nakagawa M. Yamanaka S. Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts.Genes Cells. 2009; 14: 683-694Crossref PubMed Scopus (111) Google Scholar), tumorigenesis, and early embryonic development (16Tatetsu H. Kong N.R. Chong G. Amabile G. Tenen D.G. Chai L. SALL4, the missing link between stem cells, development and cancer.Gene. 2016; 584: 111-119Crossref PubMed Scopus (51) Google Scholar). However, the underlying mechanism for such an important role remains unclear. In this study, by comparing the efficiency and dynamics of a set of nuclear factors on somatic cell reprogramming, we confirm the critical role of Sall4 on somatic cell reprogramming and identified that a new factor Cecr2, a histone acetyl-lysine reader, can promote the efficiency of somatic cell reprogramming as an effect of Sall4, attempting to improve our understanding of the epigenetic mechanisms that regulate cell fate transition. Previously, we have reported a group of 7F factors (Nanog-Esrrb-Glis1-Jdp2-Kdm2b-Sall4-Mkk6) that can reprogram mouse fibroblasts into pluripotent stem cells with a ∼10% efficiency (15Wang B. Wu L. Li D. Liu Y. Guo J. Li C. Yao Y. Wang Y. Zhao G. Wang X. Fu M. Liu H. Cao S. Wu C. Yu S. et al.Induction of pluripotent stem cells from mouse embryonic fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-sall4.Cell Rep. 2019; 27: 3473-3485.e3475Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). In order to see any synergistic or cumulative effect(s) with the classic Yamanaka factors, we performed reprogramming experiments by adding each of the seven factors into Oct4, Sox2, Klf4 (Fig. 1A), and showed that five of the seven factors promote OKS-induced reprogramming (Fig. 1B and Fig. S1, A–B). Notably, Sall4, a member of the spalt-like family members (16Tatetsu H. Kong N.R. Chong G. Amabile G. Tenen D.G. Chai L. SALL4, the missing link between stem cells, development and cancer.Gene. 2016; 584: 111-119Crossref PubMed Scopus (51) Google Scholar), is the most powerful one among them, in agreement with earlier works (17Li D. Liu J. Yang X. Zhou C. Guo J. Wu C. Qin Y. Guo L. He J. Yu S. Liu H. Wang X. Wu F. Kuang J. Hutchins A.P. et al.Chromatin accessibility dynamics during iPSC reprogramming.Cell Stem Cell. 2017; 21: 819-833.e816Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 18Thompson P.J. Norton K.A. Niri F.H. Dawe C.E. McDermid H.E. CECR2 is involved in spermatogenesis and forms a complex with SNF2H in the testis.J. Mol. Biol. 2012; 415: 793-806Crossref PubMed Scopus (19) Google Scholar). We the reprogramming dynamics for Sall4 in the of OKS-induced reprogramming with as and showed that Sall4 could promote cell generation as early as iPSC in the and efficiency comparing with reprogramming efficiency in the group (Fig. and Fig. S1, To any new or mechanism for Sall4 in the of somatic cell reprogramming, we performed for or reprogramming and for showed a but from mouse embryonic fibroblasts to embryonic stem cells (Fig. with an more to in in with the that the pluripotent genes such as and were in in (Fig. A–B). we showed that genes and genes by Sall4 (Fig. We showed the of the key pluripotent genes by in a (Fig. is that the pluripotent genes in the group in the Consistently, among the derived from Sall4 genes such as stem cell of cell and among the derived from the Sall4 genes such as to and of (Fig. We performed and showed by to modulates the chromatin structure an more (Fig. We the chromatin accessibility dynamics as we (Fig. (17Li D. Liu J. Yang X. Zhou C. Guo J. Wu C. Qin Y. Guo L. He J. Yu S. Liu H. Wang X. Wu F. Kuang J. Hutchins A.P. et al.Chromatin accessibility dynamics during iPSC reprogramming.Cell Stem Cell. 2017; 21: 819-833.e816Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). We in the of or with and conditions (Fig. we that Sall4 the of pluripotent genes such as Nanog and and of genes such as and suggesting the important role for in and critical genes (Fig. To the downstream of Sall4 for promoting reprogramming, we the for the 7F reprogramming we reported (15Wang B. Wu L. Li D. Liu Y. Guo J. Li C. Yao Y. Wang Y. Zhao G. Wang X. Fu M. Liu H. Cao S. Wu C. Yu S. et al.Induction of pluripotent stem cells from mouse embryonic fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-sall4.Cell Rep. 2019; 27: 3473-3485.e3475Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). comparing the expression we a of genes by Sall4 (Fig. showed that genes for stem cell stem cell and stem cell by Sall4 in reprogramming (Fig. We the expression of stem genes in and reprogramming and showed by for the or specific genes by Sall4 between the two (Fig. To this we identified Cecr2, and for on their expression to Sall4 in reprogramming (Fig. We these genes in the OKS-induced reprogramming and that Cecr2 is the that could promote somatic cell reprogramming (Fig. Fig. We the dynamics of iPSC by Cecr2 with and showed that Cecr2 promoted reprogramming the of reprograming (Fig. To confirm these we use as the cells and (Fig. and Fig. Consistently, Cecr2 is Sall4 in the 7F reprogramming (Fig. is Sall4 is in the reprogramming (Fig. suggest that Cecr2 may be by Sall4 To this we performed experiments with Sall4 in (Fig. and in the region of Cecr2 chromatin is with To the of these we two by two Cecr2 as and that Sall4 can with (Fig. suggesting that Sall4 the expression of Cecr2 by directly binding to the transcription region. We showed that Cecr2 can replace Sall4 in reprograming (Fig. was synergistic effect with Sall4 in OKS-induced reprogramming (Fig. showed that iPSC derived from were to in (Fig. and expression (Fig. that Cecr2 is a downstream of Sall4 in somatic cell reprogramming. To the mechanism through which Cecr2 reprogramming, we performed on and reprogramming cells and between and (Fig. pluripotent such as and have expression Cecr2 (Fig. with the we can genes and by Cecr2, (Fig. or reveals that genes by Cecr2 in such as of cell stem cell and DNA and by Cecr2 as of of (Fig. The between the and expression in that Cecr2 may regulate a specific set of To confirm we performed on and reprogramming cells and Indeed, for between and (Fig. with the the of or between the two conditions (Fig. with and in conditions (Fig. However, the chromatin pluripotent genes such as and more in the Cecr2 group in the group (Fig. suggesting that Cecr2 promoted reprogramming by chromatin structure of reprogramming. To the or the to the pluripotent network between Cecr2 and Sall4, we the from and by and and by a set of stem genes and showed that genes such as and by CECR2 and genes such as Sall4, and by genes such as and by SALL4, (Fig. We also the chromatin accessibility dynamics from and and showed that the chromatin of Cecr2 is to Sall4 group the of reprogramming (Fig. that CECR2 a significant role in chromatin in the of reprogramming. CECR2 is a multidomain transcription factor J. Liu J. Yang J. Chen Y. Chen J. S. H. L. K. D. replace Klf4 and reprogramming of mouse fibroblasts by Oct4 2011; 21: PubMed Scopus Google Scholar) that may chromatin remodeling through its in chromatin remodeling with or or in combination (Fig. To see which one is for reprogramming, we a set of as in and that the of the in of to promote reprogramming (Fig. Previously, Cecr2 was reported to the chromatin structure by forming a complex with P.J. Norton K.A. Niri F.H. Dawe C.E. McDermid H.E. CECR2 is involved in spermatogenesis and forms a complex with SNF2H in the testis.J. Mol. Biol. 2012; 415: 793-806Crossref PubMed Scopus (19) Google member of the family of and in cells, we this by (Fig. and showed that the was for this (Fig. we this by and showed by that CECR2 could could (Fig. Fig. Consistently, for showed a significant in for chromatin remodeling (Fig. Fig. that CECR2 somatic cell reprogramming by DTT chromatin To the role Cecr2 may play in and we Cecr2 by in (Fig. and the of Cecr2 (Fig. and protein (Fig. Cecr2 or to in (Fig. expression of pluripotent genes (Fig. and also the expression in (Fig. that Cecr2 is for or early embryonic We the development potential of by the cells into or by a to mouse (Fig. were in were in the group (Fig. with of (Fig. We by for derived from (Fig. The Cecr2 could be reprogramed into iPSC an efficiency of (Fig. Consistently, of Cecr2 by on the reprogramming efficiency (Fig. that Cecr2 is for iPSC However, Sall4 promotes reprogramming more in in Cecr2 (Fig. that SALL4 promotes somatic cell reprogramming by somatic reprogramming is a for the of mechanism in cell and the in medicine. A and of this is the of a set that can and iPSC generation in a and Previously, we that Sall4 is the most transcriptional factor among a new set of 7F reprogramming factor cocktails by which iPSC could be and (15Wang B. Wu L. Li D. Liu Y. Guo J. Li C. Yao Y. Wang Y. Zhao G. Wang X. Fu M. Liu H. Cao S. Wu C. Yu S. et al.Induction of pluripotent stem cells from mouse embryonic fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-sall4.Cell Rep. 2019; 27: 3473-3485.e3475Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). In this study, we the significant role of Sall4 overexpression in the classic Yamanaka factors somatic cell reprogramming and the chromatin accessibility and expression we identified Cecr2, a histone acetyl-lysine reader, is an important of SALL4 in somatic cell reprogramming. that Cecr2 as an of Sall4 to the of chromatin accessibility (Fig. which our understanding for transcription cell fate in and somatic cell reprogramming. In to the classic Yamanaka factors, a of transcriptional factors have reported to somatic cell reprogramming J. Liu J. Yang J. Chen Y. Chen J. S. H. L. K. D. replace Klf4 and reprogramming of mouse fibroblasts by Oct4 2011; 21: PubMed Scopus Google Scholar). them, Oct4 was to be the most important as Oct4 can reprogram into the pluripotent Feng B. the the of new transcription 2013; PubMed Scopus Google Scholar). Previously, Sall4 has as a factor that between stem cells, and (16Tatetsu H. Kong N.R. Chong G. Amabile G. Tenen D.G. Chai L. SALL4, the missing link between stem cells, development and cancer.Gene. 2016; 584: 111-119Crossref PubMed Scopus (51) Google Scholar), and of regulators, and targets of SALL4 were our that Sall4 showed an other reprogramming factors by a dropout in a 7F reprogramming cocktails (15Wang B. Wu L. Li D. Liu Y. Guo J. Li C. Yao Y. Wang Y. Zhao G. Wang X. Fu M. Liu H. Cao S. Wu C. Yu S. et al.Induction of pluripotent stem cells from mouse embryonic fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-sall4.Cell Rep. 2019; 27: 3473-3485.e3475Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). The of CECR2 the reprogramming factor family CECR2 has reported to be a member of an important family of chromatin and this will new into the mechanisms by which Sall4 somatic reprogramming through epigenetic in by altering chromatin such as BAF have reported to be involved in somatic reprogramming (14Singhal N. Graumann J. Wu G. Araúzo-Bravo M.J. Han D.W. Greber B. Gentile L. Mann M. Schöler H.R. Chromatin-remodeling components of the BAF complex facilitate reprogramming.Cell. 2010; 141: 943-955Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). CECR2 has reported to be involved in somatic reprogramming for the CECR2 has reported to chromatin complex with Feng B. the the of new transcription 2013; PubMed Scopus Google Scholar), suggesting that this complex may be involved in chromatin accessibility during somatic reprogramming, the somatic reprogramming is important to whether this chromatin is specific to somatic reprogramming or In is to whether mechanisms in the fate of other were with to from mouse were from mouse from of and and cells were in with and were on with or with A of cells were into was performed cell were and and by could be for to were into or a of and were a of with to were to J. Liu J. Chen Y. Yang J. Chen J. 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