Discovering How Heme Controls Genome Function Through Heme-omics
Ruiqi Liao,
Ye Zheng,
Xin Liu,
Yuannyu Zhang,
Gretchen Seim,
Nobuyuki Tanimura,
Gary M. Wilson,
Peiman Hematti,
Joshua J. Coon,
Jing Fan,
Jian Xu,
Sunduz Keles,
Emery H. Bresnick
Affiliations
Ruiqi Liao
Department of Cell and Regenerative Biology, UW-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Ye Zheng
Department of Statistics, Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Xin Liu
Children’s Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Yuannyu Zhang
Children’s Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Gretchen Seim
Department of Nutritional Sciences, Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI, USA
Nobuyuki Tanimura
Department of Cell and Regenerative Biology, UW-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Gary M. Wilson
Department of Chemistry, Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Peiman Hematti
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Joshua J. Coon
Department of Chemistry, Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Jing Fan
Department of Nutritional Sciences, Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI, USA
Jian Xu
Children’s Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Sunduz Keles
Department of Statistics, Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Corresponding author
Emery H. Bresnick
Department of Cell and Regenerative Biology, UW-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Corresponding author
Summary: 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.
