Discovering How Heme Controls Genome Function Through Heme-omics

• Published in: Cell reports (Cambridge) 2020-06, Vol.31 (13), p.107832-107832, Article 107832
• Main Authors: Liao, Ruiqi, Zheng, Ye, Liu, Xin, Zhang, Yuannyu, Seim, Gretchen, Tanimura, Nobuyuki, Wilson, Gary M., Hematti, Peiman, Coon, Joshua J., Fan, Jing, Xu, Jian, Keles, Sunduz, Bresnick, Emery H.
• Format: Article
• Language: English
• Subjects: Animals; ATAC-seq; Bach1; Base Sequence; Basic-Leucine Zipper Transcription Factors - metabolism; Cell Differentiation - genetics; chromatin; Chromatin - metabolism; Chromatin Assembly and Disassembly - genetics; erythroblast; erythroid; Erythroid Cells - cytology; Erythroid Cells - metabolism; GATA1; GATA1 Transcription Factor - metabolism; Gene Expression Regulation; Gene Regulatory Networks; Genome; heme; Heme - metabolism; Humans; Male; Mice; Models, Biological; Nucleotide Motifs - genetics; transcriptome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107832

Protein ensembles control genome function by establishing, maintaining, and deconstructing cell-type-specific chromosomal landscapes. A plethora of small molecules orchestrate cellular functions and therefore may link physiological processes with genome biology. The metabolic enzyme and hemoglobin cofactor heme induces proteolysis of a transcriptional repressor, Bach1, and regulates gene expression post-transcriptionally. However, whether heme controls genome function broadly or through prescriptive actions is unclear. Using assay for transposase-accessible chromatin sequencing (ATAC-seq), we establish a heme-dependent chromatin atlas in wild-type and mutant erythroblasts lacking enhancers that confer normal heme synthesis. Amalgamating chromatin landscapes and transcriptomes in cells with sub-physiological heme and post-heme rescue reveals parallel Bach1-dependent and Bach1-independent mechanisms that target heme-sensing chromosomal hotspots. The hotspots harbor a DNA motif demarcating heme-regulated chromatin and genes encoding proteins not known to be heme regulated, including metabolic enzymes. The heme-omics analysis establishes how an essential biochemical cofactor controls genome function and cellular physiology. [Display omitted] •Heme-omics resource is generated by amalgamating ATAC-seq and RNA-seq datasets•Parallel Bach1-dependent and independent heme mechanisms regulate genome function•A unique DNA motif demarcates heme-regulated chromatin sites•Heme-sensing hotspots reveal new dimensions in genome biology and cellular regulation Liao et al. generate a heme-regulated chromatin atlas by amalgamating ATAC-seq and RNA-seq datasets from cells with normal and sub-physiological heme, and they identify parallel Bach1-dependent and Bach1-independent mechanisms that target heme-sensing chromatin hotspots. The hotspots harbor a DNA motif demarcating heme-regulated chromatin and genes not known to be heme regulated.