Early Enhancer Establishment and Regulatory Locus Complexity Shape Transcriptional Programs in Hematopoietic Differentiation

Overview

Journal Nat Genet

Specialty Genetics

Date 2015 Sep 22

PMID 26390058

Citations 53

Authors

Alvaro J Gonzalez

Manu Setty

Christina S Leslie

Affiliations

Soon will be listed here.

Abstract

We carried out an integrative analysis of enhancer landscape and gene expression dynamics during hematopoietic differentiation using DNase-seq, histone mark ChIP-seq and RNA sequencing to model how the early establishment of enhancers and regulatory locus complexity govern gene expression changes at cell state transitions. We found that high-complexity genes-those with a large total number of DNase-mapped enhancers across the lineage-differ architecturally and functionally from low-complexity genes, achieve larger expression changes and are enriched for both cell type-specific and transition enhancers, which are established in hematopoietic stem and progenitor cells and maintained in one differentiated cell fate but lost in others. We then developed a quantitative model to accurately predict gene expression changes from the DNA sequence content and lineage history of active enhancers. Our method suggests a new mechanistic role for PU.1 at transition peaks during B cell specification and can be used to correct assignments of enhancers to genes.

Citing Articles

Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart.

Read D, Booth G, Daza R, Jackson D, Gladden R, Srivatsan S Commun Biol. 2024; 7(1):1052.

PMID: 39187646 PMC: 11347658. DOI: 10.1038/s42003-024-06582-y.

Quantifying cell-state densities in single-cell phenotypic landscapes using Mellon.

Otto D, Jordan C, Dury B, Dien C, Setty M Nat Methods. 2024; 21(7):1185-1195.

PMID: 38890426 DOI: 10.1038/s41592-024-02302-w.

Quantifying Cell-State Densities in Single-Cell Phenotypic Landscapes using Mellon.

Otto D, Jordan C, Dury B, Dien C, Setty M bioRxiv. 2023; .

PMID: 37502954 PMC: 10369887. DOI: 10.1101/2023.07.09.548272.

Oncogenic K-Ras suppresses global miRNA function.

Shui B, Beyett T, Chen Z, Li X, La Rocca G, Gazlay W Mol Cell. 2023; 83(14):2509-2523.e13.

PMID: 37402366 PMC: 10527862. DOI: 10.1016/j.molcel.2023.06.008.

SeATAC: a tool for exploring the chromatin landscape and the role of pioneer factors.

Gong W, Dsouza N, Garry D Genome Biol. 2023; 24(1):125.

PMID: 37218013 PMC: 10204251. DOI: 10.1186/s13059-023-02954-5.

References

Perrotti D, Melotti P, Skorski T, Casella I, Peschle C, Calabretta B . Overexpression of the zinc finger protein MZF1 inhibits hematopoietic development from embryonic stem cells: correlation with negative regulation of CD34 and c-myb promoter activity. Mol Cell Biol. 1995; 15(11):6075-87. PMC: 230859. DOI: 10.1128/MCB.15.11.6075. View

Hnisz D, Abraham B, Lee T, Lau A, Saint-Andre V, Sigova A . Super-enhancers in the control of cell identity and disease. Cell. 2013; 155(4):934-47. PMC: 3841062. DOI: 10.1016/j.cell.2013.09.053. View

Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A . Integrative analysis of 111 reference human epigenomes. Nature. 2015; 518(7539):317-30. PMC: 4530010. DOI: 10.1038/nature14248. View

Schoenfelder S, Furlan-Magaril M, Mifsud B, Tavares-Cadete F, Sugar R, Javierre B . The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements. Genome Res. 2015; 25(4):582-97. PMC: 4381529. DOI: 10.1101/gr.185272.114. View

Shen Y, Yue F, McCleary D, Ye Z, Edsall L, Kuan S . A map of the cis-regulatory sequences in the mouse genome. Nature. 2012; 488(7409):116-20. PMC: 4041622. DOI: 10.1038/nature11243. View

Robinson M, McCarthy D, Smyth G . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009; 26(1):139-40. PMC: 2796818. DOI: 10.1093/bioinformatics/btp616. View

Anderson E, Hill R . Long range regulation of the sonic hedgehog gene. Curr Opin Genet Dev. 2014; 27:54-9. DOI: 10.1016/j.gde.2014.03.011. View

Zhu J, Adli M, Zou J, Verstappen G, Coyne M, Zhang X . Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell. 2013; 152(3):642-54. PMC: 3563935. DOI: 10.1016/j.cell.2012.12.033. View

Zheng Y, Josefowicz S, Chaudhry A, Peng X, Forbush K, Rudensky A . Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010; 463(7282):808-12. PMC: 2884187. DOI: 10.1038/nature08750. View

10.

Sanyal A, Lajoie B, Jain G, Dekker J . The long-range interaction landscape of gene promoters. Nature. 2012; 489(7414):109-13. PMC: 3555147. DOI: 10.1038/nature11279. View

11.

Thurman R, Rynes E, Humbert R, Vierstra J, Maurano M, Haugen E . The accessible chromatin landscape of the human genome. Nature. 2012; 489(7414):75-82. PMC: 3721348. DOI: 10.1038/nature11232. View

12.

Pott S, Lieb J . What are super-enhancers?. Nat Genet. 2014; 47(1):8-12. DOI: 10.1038/ng.3167. View

13.

Pan Z, Hetherington C, Zhang D . CCAAT/enhancer-binding protein activates the CD14 promoter and mediates transforming growth factor beta signaling in monocyte development. J Biol Chem. 1999; 274(33):23242-8. DOI: 10.1074/jbc.274.33.23242. View

14.

Gaujoux R, Seoighe C . A flexible R package for nonnegative matrix factorization. BMC Bioinformatics. 2010; 11:367. PMC: 2912887. DOI: 10.1186/1471-2105-11-367. View

15.

Dobin A, Davis C, Schlesinger F, Drenkow J, Zaleski C, Jha S . STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2012; 29(1):15-21. PMC: 3530905. DOI: 10.1093/bioinformatics/bts635. View

16.

Xi H, Shulha H, Lin J, Vales T, Fu Y, Bodine D . Identification and characterization of cell type-specific and ubiquitous chromatin regulatory structures in the human genome. PLoS Genet. 2007; 3(8):e136. PMC: 1950163. DOI: 10.1371/journal.pgen.0030136. View

17.

Dowen J, Fan Z, Hnisz D, Ren G, Abraham B, Zhang L . Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell. 2014; 159(2):374-387. PMC: 4197132. DOI: 10.1016/j.cell.2014.09.030. View

18.

Bernstein B, Mikkelsen T, Xie X, Kamal M, Huebert D, Cuff J . A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006; 125(2):315-26. DOI: 10.1016/j.cell.2006.02.041. View

19.

Setty M, Leslie C . SeqGL Identifies Context-Dependent Binding Signals in Genome-Wide Regulatory Element Maps. PLoS Comput Biol. 2015; 11(5):e1004271. PMC: 4446265. DOI: 10.1371/journal.pcbi.1004271. View

20.

Huang D, Sherman B, Lempicki R . Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2008; 37(1):1-13. PMC: 2615629. DOI: 10.1093/nar/gkn923. View