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Enhancer Dependence of Cell-Type–Specific Gene Expression Increases with Developmental Age

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Enhancer Dependence of Cell-Type–Specific Gene Expression Increases with Developmental Age Enhancer dependence of cell-type–specific gene expression increases with developmental age Wenqing Caia,1, Jialiang Huanga,b,c,1, Qian Zhua,b, Bin E. Lia, Davide Seruggiaa, Pingzhu Zhoud, Minh Nguyena, Yuko Fujiwaraa, Huafeng Xiea, Zhenggang Yangc, Danni Hongc, Pengfei Renc, Jian Xue, William T. Pud, Guo-Cheng Yuanb,2, and Stuart H. Orkina,f,2 aCancer and Blood Disorders Center, Boston Children’s Hospital and Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; bDepartment of Pediatric Oncology, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; cState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; dDepartment of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02215; eChildren’s Medical Center Research Institute, Department of Pediatrics, University of Texas at Southwestern Medical Center, Dallas, TX 75390; and fHoward Hughes Medical Institute, Harvard Medical School, Boston, MA 02115 Contributed by Stuart H. Orkin, July 21, 2020 (sent for review May 4, 2020; reviewed by Hongkai Ji and Ellen V. Rothenberg) How overall principles of cell-type–specific gene regulation (the EryP cells emerge in blood islands and mature as a semi- “logic”) may change during ontogeny is largely unexplored. We synchronous cohort in the circulation. EryD cells, which are adult compared transcriptomic, epigenomic, and three-dimensional (3D) type, are generated within the fetal liver and later in the postnatal genomic profiles in embryonic (EryP) and adult (EryD) erythro- bone marrow (9). Gata1 plays a central role in the regulation of blasts. Despite reduced chromatin accessibility compared to EryP, erythroid-specific genes in both EryP and EryD lineages and is distal chromatin of EryD is enriched in H3K27ac, Gata1, and Myb required for their differentiation (11, 12). Gata1 collaborates with occupancy. EryP-/EryD-shared enhancers are highly correlated other critical TFs, including Scl/Tal1, Ldb1, Fog1, and Lmo2 (7, 9, with red blood cell identity genes, whereas cell-type–specific reg- 13). Knockout of each of these genes leads to defects in EryP and ulation employs different cis elements in EryP and EryD cells. In EryD cells (7, 9, 13). In contrast, the loss of Myb, which is expressed contrast to EryP-specific genes, which exhibit promoter-centric selectively in definitive type cells, impairs proliferation and differ- regulation through Gata1, EryD-specific genes rely more on distal entiation of EryD, sparing EryP cells (8). Given the different reli- enhancers for regulation involving Myb-mediated enhancer acti- ance of EryP and EryD cells on TFs for their development, we have – vation. Gata1 HiChIP demonstrated an overall increased enhancer asked whether these related, but distinct, cell lineages in ontogeny promoter interactions at EryD-specific genes, whereas genome differ in their fundamental regulatory organization and logic. editing in selected loci confirmed distal enhancers are required To address this question, we isolated mouse EryP and EryD for gene expression in EryD but not in EryP. Applying a metric erythroblasts and characterized transcriptomes, chromatin accessi- for enhancer dependence of transcription, we observed a progres- bility, histone modifications, transcription factor (TF) occupancies, sive reliance on cell-specific enhancers with increasing ontogenetic and three-dimensional (3D) chromatin interactions. We observed age among diverse tissues of mouse and human origin. Our find- that distal enhancer-dependent, cell-type–specific gene regulation ings highlight fundamental and conserved differences at distinct developmental stages, characterized by simpler promoter-centric regulation of cell-type–specific genes in embryonic cells and in- Significance creased combinatorial enhancer-driven control in adult cells. Gene regulatory logic reflects the occupancy of cis elements by enhancer | erythropoiesis | HiChIP | GATA1 | Myb transcription factors and the configuration of promoters and en- hancers. As the majority of genome-wide analyses have focused on adult cells, scant attention has been paid to embryonic cells, nteractions between chromatin and nuclear regulatory factors other than embryonic stem cells. Focusing on genome-wide establish gene expression programs during development (1). I comparative analyses of two stages of erythroblasts, we discov- Whereas chromatin landscapes have been elucidated by genome- ered that regulation of embryonic-specific genes is promoter- wide chromatin profiling methods in numerous adult cell types (2, centric through Gata1, whereas adult-specific control is combina- 3), scant attention has been paid to embryonic cell types in human torial enhancer-driven and requires Myb, which is confirmed by and mouse systems, other than embryonic stem cells (ESCs). Despite increased enhancer–promoter interactions of adult specific genes. well-characterized gene regulatory networks (GRNs) in embryos of Extending genome-wide comparative analyses more broadly to some model animals (including Drosophila melanogaster,seaurchin, available datasets of diverse mouse and human cells and tissues, and chick) (4–6), whether the organization, or “logic,” of gene reg- we conclude that the progressively increased enhancer depen- ulation differs between embryonic and adult cells remains to be dence of cell-type–specific genes with developmental age is explored. We began by examining these issues in the context of conserved during development. functionally analogous blood cells of two different stages of ontog- Author contributions: W.C., G.-C.Y., and S.H.O. designed research; W.C., J.H., B.E.L., D.S., eny, and then extended our findings more broadly to other cell types. P.Z., M.N., Y.F., Z.Y., D.H., and P.R. performed research; H.X., J.X., and W.T.P. contributed Primitive (EryP; also referred to as “embryonic”) and defini- new reagents/analytic tools; W.C., J.H., Q.Z., and S.H.O. analyzed data; and W.C., G.-C.Y., tive (EryD; also referred to as “adult”) erythroid cells constitute and S.H.O. wrote the paper. distinct, temporally overlapping lineages with similar in vivo Reviewers: H.J., Johns Hopkins University; and E.V.R., California Institute of Technology. function and provide a unique opportunity to explore chromatin The authors declare no competing interest. state at two different stages of ontogeny. Prior molecular studies This open access article is distributed under Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC-ND). have identified master erythroid-lineage transcription factors 1 — — W.C. and J.H. contributed equally to this work. (TFs) Gata1, Tal1, and Klf1 and several adult-specific fac- 2 – To whom correspondence may be addressed. Email: [email protected] or tors, namely Bcl11a, Sox6, and Myb (7 10). Whereas transcrip- [email protected]. tional mechanisms have been studied extensively in EryD cells, This article contains supporting information online at https://www.pnas.org/lookup/suppl/ we are unaware of analyses in EryP cells, which arise in the yolk doi:10.1073/pnas.2008672117/-/DCSupplemental. sac as a distinct lineage. First published August 19, 2020. 21450–21458 | PNAS | September 1, 2020 | vol. 117 | no. 35 www.pnas.org/cgi/doi/10.1073/pnas.2008672117 Downloaded by guest on October 1, 2021 is overall greater in EryD than in EryP, while cell-type–specific To evaluate whether the different accessibility at distal regions gene regulation in EryP is relatively promoter-centric, using in EryP and EryD relates to putative enhancer activity, we per- Gata1. We hypothesized that these features reflect inherent dif- formed chromatin immunoprecipitation sequencing (ChIP-seq) ferences between embryonic cells and more diverse, long-lived for H3K27ac. As expected, H3K27ac distributed across both adult cells. Analyses of available datasets of diverse mouse and proximal and distal regions (SI Appendix, Fig. S1 E and F). In human cells and tissues provided further support for the unex- contrast to the greater overall accessibility in EryP, we identified pected finding that cell-type–specific regulatory logic changes 5,137 EryP-specific H3K27ac peaks and 7,164 EryD-specific with ontogeny. peaks (Fig. 2A and SI Appendix, Fig. S2A). While the numbers of cell-type–specific H3K27ac peaks at proximal regions were Results comparable between EryD and EryP (1,652 vs. 1,841), we ob- EryD-Specific Distal Accessible Chromatin Is Enriched for Active served more cell-type–specific distal H3K27ac peaks in EryD Enhancers. CD71+/Ter119+ EryP and EryD cells were isolated than in EryP (5,512 vs. 3,296) (Fig. 2A). We categorized the by FACS from embryonic day (E)10.5 embryonic peripheral blood distal accessible regions based on H3K27ac peaks into two sub- and E13.5 fetal liver, respectively (14). We profiled transcriptomes, groups, active (with H3K27ac) or open only (without H3K27ac). chromatin accessibility, histone modifications, and TF occupancies A small fraction (22%) of EryP-specific distal accessible regions (Fig. 1A). Identity of the respective cell populations was assessed by were active, which was similar to that in shared distal accessible the expression of globin and TFs characteristic of each lineage regions (25%) (Fig. 2B). In contrast, the percentage was much (SI Appendix, Figs. S1 A–C). Transcriptome analyses revealed greater (65%) in EryD-specific distal accessible regions (Fig. 2B 943 EryP-specific
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