Methylation of Gata3 Protein at Arg-261 Regulates Transactivation of the Il5 Gene in T Helper 2 Cells

Hosokawa, Hiroyuki; Kato, Mayumi; Tohyama, Hiroyuki; Tamaki, Yuko; Endo, Yusuke; Kimura, Motoko; Tumes, Damon J.; Motohashi, Shinichiro; Matsumoto, Masaki; Nakayama, Keiichi I.; Tanaka, Tomoaki; Nakayama, Toshinori

doi:10.1074/jbc.m114.621524

“…GATA factors utilize coregulators to confer activation or repression and are controlled by signaling mechanisms that induce phosphorylation , acetylation , methylation , and sumoylation . How biochemical constituents, such as metal ions and metabolic intermediates, impact specific steps in GATA factor function is largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

Mechanism governing heme synthesis reveals a GATA factor/heme circuit that controls differentiation

Tanimura

¹

,

Miller

²

,

Igarashi

³

et al. 2015

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Metal ion-containing macromolecules have fundamental roles in essentially all biological processes throughout the evolutionary tree. For example, iron-containing heme is a cofactor in enzyme catalysis and electron transfer and an essential hemoglobin constituent. To meet the intense demand for hemoglobin assembly in red blood cells, the cell type-specific factor GATA-1 activates transcription of Alas2, encoding the rate-limiting enzyme in heme biosynthesis, 5-aminolevulinic acid synthase-2 (ALAS-2). Using genetic editing to unravel mechanisms governing heme biosynthesis, we discovered a GATA factor-and heme-dependent circuit that establishes the erythroid cell transcriptome. CRISPR/Cas9-mediated ablation of two Alas2 intronic cis elements strongly reduces GATA-1-induced Alas2 transcription, heme biosynthesis, and surprisingly, GATA-1 regulation of other vital constituents of the erythroid cell transcriptome. Bypassing ALAS-2 function in Alas2 cis element-mutant cells by providing its catalytic product 5-aminolevulinic acid rescues heme biosynthesis and the GATA-1-dependent genetic network. Heme amplifies GATA-1 function by downregulating the heme-sensing transcriptional repressor Bach1 and via a Bach1-insensitive mechanism. Through this dual mechanism, heme and a master regulator collaborate to orchestrate a cell type-specific transcriptional program that promotes cellular differentiation.

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“…Recently, several groups reported that post-translational modifications of GATA3 regulate its functions (Cook and Miller 2010; Kitagawa et al 2014; Hosokawa et al 2015; Hosokawa et al 2016). Phosphorylation and acetylation regulate both stability and transcriptional activity of the related GATA1 factor (Hernandez-Hernandez et al 2006).…”

Section: Gata3 and The Establishment Of A T-cell Specific Regulatory mentioning

confidence: 99%

Cytokines, Transcription Factors, and the Initiation of T-Cell Development

Hosokawa

¹

,

Rothenberg

²

2017

Cold Spring Harb Perspect Biol

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Multipotent blood progenitor cells migrate into the thymus and initiate the T cell differentiation program. T cell progenitor cells gradually acquire T cell characteristics while shedding their multipotentiality for alternative fates. This process is supported by extracellular signaling molecules, including Notch ligands and cytokines, provided by the thymic microenvironment. T cell development is associated with dynamic change of gene regulatory networks of transcription factors, which interact with these environmental signals. Together with Notch or pre-TCR signaling, cytokines always control proliferation, survival and differentiation of early T cells, but little is known regarding their crosstalk with transcription factors. However, recent results suggest ways that cytokines expressed in distinct intrathymic niches can specifically modulate key transcription factors. This review discusses how stage-specific roles of cytokines and transcription factors can jointly guide development of early T cells.

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“…GATA factors utilize coregulators to confer activation or repression [27] and are controlled by signaling mechanisms that induce phosphorylation [51][52][53], acetylation [54], methylation [55], and sumoylation [56]. How biochemical constituents, such as metal ions and metabolic intermediates, impact specific steps in GATA factor function is largely unexplored.…”

Section: S L C 4 a 1 E P B 4 9 A H S P G A T A 2 E I F 2 S 1 E I F mentioning

confidence: 99%

Mechanism Governing Heme Synthesis Reveals a GATA Factor-Heme Circuit That Controls Differentiation

Bresnick

¹

,

Tanimura

²

,

Miller

³

et al. 2015

Blood

0

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Metal ion-containing macromolecules have fundamental roles in essentially all biological processes throughout the evolutionary tree. For example, iron-containing heme is a cofactor in enzyme catalysis and electron transfer and an essential hemoglobin constituent. To meet the intense demand for hemoglobin assembly in red blood cells, the cell type-specific factor GATA-1 activates transcription of Alas2, encoding the rate-limiting enzyme in heme biosynthesis, 5-aminolevulinic acid synthase-2 (ALAS-2). Using genetic editing to unravel mechanisms governingheme biosynthesis, we discovered a GATA factor- and heme-dependent circuit that establishes the erythroid cell transcriptome. CRISPR/Cas9-mediated ablation of two Alas2 intronic cis-elements strongly reduced GATA-1-induced Alas2 transcription and heme biosynthesis. Surprisingly, the cis-element ablation impaired GATA-1 regulation of other vital constituents of the erythroid cell transcriptome, including components mediating autophagy and nutrient transport. Bypassing ALAS-2 function in Alas2 cis-element-mutant cells by providing its catalytic product 5-aminolevulinic acid rescued heme biosynthesis and a sector of the GATA-1-dependent genetic network. A component of the gene cohort deregulated in heme deficiency could not be reactivated by rescuing heme biosynthesis, and we are testing whether irreversible changes in their chromatin states upon heme deficiency confer stable repression. Heme amplified GATA-1 function by downregulating the heme-sensing transcriptional repressor Bach1 and via a Bach1-insensitive mechanism. Based on this dual mechanism, we developed a paradigm in which a fundamentally critical process in hematology, heme biosynthesis, is intricately linked to the actions of a quintessential regulator of a cell type-specific transcriptional program that controls cellular differentiation. As known mechanistic insights into GATA factor mechanisms do not predict whether a GATA-1 target gene will be heme- or Bach1-sensitive, these studies revealed a new mode of GATA factor function that controls erythroid cell development and function. We will discuss how this mechanism is being dissected in biologically important murine and human systems. Disclosures No relevant conflicts of interest to declare.

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Methylation of Gata3 Protein at Arg-261 Regulates Transactivation of the Il5 Gene in T Helper 2 Cells

Cited by 30 publications

References 45 publications

Mechanism governing heme synthesis reveals a GATA factor/heme circuit that controls differentiation

Mechanism governing heme synthesis reveals a GATA factor/heme circuit that controls differentiation

Cytokines, Transcription Factors, and the Initiation of T-Cell Development

Mechanism Governing Heme Synthesis Reveals a GATA Factor-Heme Circuit That Controls Differentiation

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