Discovering How Heme Controls Genome Function Through Heme-omics

Liao, Ruiqi; Zheng, Yi; Liu, Xin; Zhang, Yuannyu; Seim, Gretchen; Tanimura, Nobuyuki; Wilson, Gary; Hematti, Peiman; Coon, Joshua J.; Fan, Jianqing; Xu, Jian; Keleş, Sündüz; Bresnick, Emery H.

doi:10.1016/j.celrep.2020.107832

Cited by 26 publications

(28 citation statements)

References 73 publications

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“…Related SLC family members Slc7a12 , Slc22a28 and Slc22a29 lacked ATAC-seq, GATA2 and GATA1 ChIP-seq peaks and served as negative controls ( Fig 4B ). These SLC genes, including Slc29a1 , shared intronic GATA1 and GATA2 occupancy [ 38 ] that overlaps with accessible chromatin identified by our prior ATAC-seq analysis [ 39 ] and candidate cis -regulatory elements (cCREs) [ 41 ], providing evidence for GATA factor-mediated transcriptional regulation through the intronic sequences.…”

Section: Resultsmentioning

confidence: 99%

“… (A) Model depicting direct GATA2 regulation via intronic enhancers with WGATAR and E-box motifs. (B) ATAC-seq (GEO GSE114996) [ 39 ] and ChIP-seq profiles (GEO GSE30142, GEO GSE29196) [ 38 , 40 ] of GATA1/2 co-regulated SLC genes ( Slc29a1 , Slc41a3 , Slc7a1 , Slc11a2 , Slc4a1 , Slc43a3 , Slc25a44 , and Slc22a23 ), and control genes ( Slc7a12 , Slc22a28 and Slc22a29 ) in G1E or G1E-ER-GATA1 cells. The GATA2 ChIP-seq peak is enlarged to illustrate candidate cis -regulatory elements (black bars)[ 41 ], WGATAR motifs (underlined, red text), and E-Box motifs (underlined, blue text).…”

Section: Resultsmentioning

confidence: 99%

“…We parsed the GATA2/GATA1-co-regulated SLC cohort into four groups of GATA2-upregulated/GATA1-upregulated, GATA2-upregulated/GATA1-downregulated, GATA2-downregulated/GATA1-upregulated, and GATA2-downregulated/GATA1-downregulated (S1 Table). We analyzed GATA2 (in G1E proerythroblasts; GEO GSE29196) and GATA1 (in differentiated G1E-ER-GATA1 cells; GEO GSE30142) occupancy and ATAC-seq profiles (in differentiated G1E-ER-GATA1 cells; GEO GSE114996) for each gene [38][39][40]. For the GATA2-upregulated genes, GATA2-occupied 21 of 28 SLCs.…”

Section: Plos Geneticsmentioning

confidence: 99%

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GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism

Zwifelhofer

Cai²,

Liao

et al. 2020

PLoS Genet

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Developmental-regulatory networks often include large gene families encoding mechanistically-related proteins like G-protein-coupled receptors, zinc finger transcription factors and solute carrier (SLC) transporters. In principle, a common mechanism may confer expression of multiple members integral to a developmental process, or diverse mechanisms may be deployed. Using genetic complementation and enhancer-mutant systems, we analyzed the 456 member SLC family that establishes the small molecule constitution of cells. This analysis identified SLC gene cohorts regulated by GATA1 and/or GATA2 during erythroid differentiation. As >50 SLC genes shared GATA factor regulation, a common mechanism established multiple members of this family. These genes included Slc29a1 encoding an equilibrative nucleoside transporter (Slc29a1/ENT1) that utilizes adenosine as a preferred substrate. Slc29a1 promoted erythroblast survival and differentiation ex vivo. Targeted ablation of murine Slc29a1 in erythroblasts attenuated erythropoiesis and erythrocyte regeneration in response to acute anemia. Our results reveal a GATA factor-regulated SLC ensemble, with a nucleoside transporter component that promotes erythropoiesis and prevents anemia, and establish a mechanistic link between GATA factor and adenosine mechanisms. We propose that integration of the GATA factor-adenosine circuit with other components of the GATA factor-regulated SLC ensemble establishes the small molecule repertoire required for progenitor cells to efficiently generate erythrocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Plos Geneticsmentioning

confidence: 99%

See 1 more Smart Citation

GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism

Zwifelhofer

Cai²,

Liao

et al. 2020

PLoS Genet

Self Cite

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“…Apart from its canonical functioning as an enzymatic cofactor, haem also serves as a signalling molecule regulating the expression of gene transcripts [35]. We have previously described positive regulatory mechanisms in the tick midgut, which were mediated by iron or haem signalling [3,19,33,36].…”

Section: Discussionmentioning

confidence: 99%

Haem-responsive gene transporter enables mobilization of host haem in ticks

et al. 2021

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Ticks, notorious blood-feeders and disease-vectors, have lost a part of their genetic complement encoding haem biosynthetic enzymes and are, therefore, dependent on the acquisition and distribution of host haem. Solute carrier protein SLC48A1, aka haem-responsive gene 1 protein (HRG1), has been implicated in haem transport, regulating the availability of intracellular haem. HRG1 transporter has been identified in both free-living and parasitic organisms ranging from unicellular kinetoplastids, nematodes, up to vertebrates. However, an HRG1 homologue in the arthropod lineage has not yet been identified. We have identified a single HRG1 homologue in the midgut transcriptome of the tick Ixodes ricinus, denoted as Ir HRG, and have elucidated its role as a haem transporter. Data from haem biosynthesis-deficient yeast growth assays, systemic RNA interference and the evaluation of gallium protoporphyrin IX-mediated toxicity through tick membrane feeding clearly show that Ir HRG is the bona fide tetrapyrrole transporter. We argue that during evolution, ticks profited from retaining a functional hrg1 gene in the genome because its protein product facilitates host haem escort from intracellularly digested haemoglobin, rendering haem bioavailable for a haem-dependent network of enzymes.

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“…Values were normalized to 18S rRNA expression. ( F ) Chromatin state (ATAC-seq) in G1E-ER-GATA1 cells (dataset from: ( 38 )), GATA1 and GATA2 occupancy at Dis3 and Bora loci in mouse and human cells ( 39–41 ). Statistically significant differences are indicated * P < 0.05, ** P < 0.01, *** P < 0.001 using two-tailed unpaired Student's t -test.…”

Section: Introductionmentioning

confidence: 99%

RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis

Mehta

Andrade

Matson

et al. 2021

Nucleic Acids Research

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Cellular differentiation requires vast remodeling of transcriptomes, and therefore machinery mediating remodeling controls differentiation. Relative to transcriptional mechanisms governing differentiation, post-transcriptional processes are less well understood. As an important post-transcriptional determinant of transcriptomes, the RNA exosome complex (EC) mediates processing and/or degradation of select RNAs. During erythropoiesis, the erythroid transcription factor GATA1 represses EC subunit genes. Depleting EC structural subunits prior to GATA1-mediated repression is deleterious to erythroid progenitor cells. To assess the importance of the EC catalytic subunits Dis3 and Exosc10 in this dynamic process, we asked if these subunits function non-redundantly to control erythropoiesis. Dis3 or Exosc10 depletion in primary murine hematopoietic progenitor cells reduced erythroid progenitors and their progeny, while sparing myeloid cells. Dis3 loss severely compromised erythroid progenitor and erythroblast survival, rendered erythroblasts hypersensitive to apoptosis-inducing stimuli and induced γ-H2AX, indicative of DNA double-stranded breaks. Dis3 loss-of-function phenotypes were more severe than those caused by Exosc10 depletion. We innovated a genetic rescue system to compare human Dis3 with multiple myeloma-associated Dis3 mutants S447R and R750K, and only wild type Dis3 was competent to rescue progenitors. Thus, Dis3 establishes a disease mutation-sensitive, cell type-specific survival mechanism to enable a differentiation program.

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Discovering How Heme Controls Genome Function Through Heme-omics

Cited by 26 publications

References 73 publications

GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism

GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism

Haem-responsive gene transporter enables mobilization of host haem in ticks

RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis

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