Epigenetic signals, p-values This composite track, "Signal p-values", provides access and visualization to the epigenetic signals as p-values for deviation from the expectation of a negative binomial distribution.
In "dense" mode, the display gives a compact view of the level of epigenetic signal for each feature in each cell type. In "full" mode, the normalized signal strength is shown as a continuous, variable signal. Users have options for setting the y-axis on the Track Settings page of each composite track.
The track names give an abbreviation for the blood cell type and replicate number (r1 or r2).
Mouse primary blood cells purified predominantly using cell surface markers include: LSK = Lin-Sca1+Kit+ cells from mouse bone marrow containing hematopoietic stem and progenitor cells, CMP = common myeloid progenitor cell, MEP = megakaryocyte-erythrocyte progenitor cell, ERY = erythroblast, GMP = granulocyte monocyte progenitor cell, MON = monocyte, NEU = neutrophil, CLP = common lymphoid progenitor cell, B = B cell, NK = natural killer cell, T_CD4 = CD4+ T cell, T_CD8 = CD8+ T cell, CFUE = colony forming unit erythroid, fl = designates ERY derived from fetal liver, ad = designates ERY derived from adult bone marrow, CFUMK = colony forming unit megakaryocyte, iMK = immature megakaryocyte, MK_fl = megakaryocyte derived from fetal liver. AVE is a track with state assignments based on the average signal for each epigenetic feature across cell types.
Data from several immortalized cell lines were included. The G1E cells are an immortalized, GATA1-null cell line derived from mouse embryonic stem cells by gene targeting; these cells proliferate in culture as immature erythroid progenitor cells (Weiss, Yu, Orkin 1997). A stable subline of these cells, called G1E-ER4, undergoes terminal erythroid maturation when GATA1 function is restored as an activatable fusion of GATA1 to the ligand-binding domain of the estrogen receptor (ER). Untreated G1E-ER4 cells, carrying the inactive GATA1-ER, proliferate without differentiation, but treatment with estradiol (E2) activates the hybrid protein, effectively complementing the GATA1 loss-of-function and allowing synchronous erythroid differentiation and maturation (Gregory et al. 1999). An additional cell line model used here are murine erythroleukemia (MEL) cells, which can be chemically induced to mature into erythroblast-like cells with increased hemoglobin (iMEL). HPC7 cells are an immortalized line that serves as a model for mouse hematopoietic progenitor cells (Pinto do O 2002). These cells are capable of differentiation in vitro into more mature myeloid cells. CH12 cells are an immortalized line that is a model for mouse B cells; the epigenetic data on CH12 cells were used to generate the B cell epigenetic state annotation.
The genome-wide signals for the epigenetic features were normalized across cell types using the S3V2 version of S3norm in the pipeline S3V2-IDEAS (Xiang et al. 2020 and 2021). The S3V2 method was developed to normalize the signal to bring out peaks without inflating the background while also denoising the data.
The data normalization was done by Guanjue Xiang. The data downloads, re-mapping and processing, generation of the tracks displayed, and development of the track hub were done by Belinda Giardine.
Gregory T, Yu C, Ma A, Orkin SH, Blobel GA, Weiss MJ. GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression. Blood. 1999; 94:87-96. PMID: 10381501.
Heuston EF, Keller CA, Lichtenberg J, Giardine B, Anderson SM; NIH Intramural Sequencing Center; Hardison RC, Bodine DM. Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points. Epigenetics Chromatin. 2018 May 28;11(1):22. PMID: 29807547; PMCID: PMC5971425.
Pinto do O P, Richter K, Carlsson L. Hematopoietic progenitor/stem cells immortalized by Lhx2 generate functional hematopoietic cells in vivo. Blood. 2002 Jun 1;99(11):3939-46. doi: 10.1182/blood.v99.11.3939. PMID: 12010792.
Weiss MJ, Yu C, Orkin SH. Erythroid-cell-specific properties of transcription factor GATA-1 revealed by phenotypic rescue of a gene-targeted cell line. Mol Cell Biol. 1997; 17:1642-1651. PMID: 9032291; PMCID: PMC231889.
Xiang G, Keller CA, Heuston E, Giardine BM, An L, Wixom AQ, Miller A, Cockburn A, Sauria MEG, Weaver K, Lichtenberg J, Göttgens B, Li Q, Bodine D, Mahony S, Taylor J, Blobel GA, Weiss MJ, Cheng Y, Yue F, Hughes J, Higgs DR, Zhang Y, Hardison RC. An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis. Genome Res. 2020 Mar;30(3):472-484. PMID: 32132109; PMCID: PMC7111515.
Xiang G, Keller CA, Giardine B, An L, Li Q, Zhang Y, Hardison RC. S3norm: simultaneous normalization of sequencing depth and signal-to-noise ratio in epigenomic data. Nucleic Acids Res. 2020 May 7;48(8):e43. doi:10.1093/nar/gkaa105. PMID: 32086521; PMCID: PMC7192629.
Xiang G, Giardine BM, Mahony S, Zhang Y, Hardison RC. S3V2-IDEAS: a package for normalizing, denoising and integrating epigenomic datasets across different cell types. Bioinformatics. 2021 Sep 29;37(18):3011-3013. doi:10.1093/bioinformatics/btab148. PMID: 33681991; PMCID: PMC8479670.
Xiang G, He X, Giardine BM, Isaac KJ, Taylor DJ, McCoy RC, Jansen C, Keller CA, Wixom AQ, Cockburn A, Miller A, Qi Q, He Y, Li Y, Lichtenberg J, Heuston EF, Anderson SM, Luan J, Vermunt MW, Yue F, Sauria MEG, Schatz MC, Taylor J, Göttgens B, Hughes JR, Higgs DR, Weiss MJ, Cheng Y, Blobel GA, Bodine DM, Zhang Y, Li Q, Mahony S, Hardison RC. Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes. Genome Res. 2024 Aug 20;34(7):1089-1105. PMID: 38951027; PMCID: PMC11368181.
These data are available for use without restrictions.
Ross Hardison rch8@psu.edu