Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands

Toshiyuki Tsunoda, Yasuo Takashima, Yoko Tanaka, Takahiro Fujimoto, Keiko Doi, Yumiko Hirose, Midori Koyanagi, Yasuhiro Yoshida, Tadashi Okamura, Masahide Kuroki, Takehiko Sasazuki, Senji Shirasawa

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

TAL1 plays pivotal roles in vascular and hematopoietic developments throughthe complex with LMO2 andGATA1.Hemangioblasts, which have a differentiation potential for both endothelial and hematopoietic lineages, arise in the primitive streak and migrate into the yolk sac to form blood islands, where primitive hematopoiesis occurs. ZFAT (a zinc-finger gene in autoimmune thyroid disease susceptibility region / an immune-related transcriptional regulator containing 18 C2H2-type zinc-finger domains and one AT-hook) was originally identified as an immune-related transcriptional regulator containing 18 C2H2-type zinc-finger domains and one AT-hook, and is highly conserved among species. ZFAT is thought to be a critical transcription factor involved in immune-regulation and apoptosis; however, developmental roles for ZFAT remain unknown. Here we show that Zfat-deficient (Zfat-/-) mice are embryonic-lethal,with impaired differentiation of hematopoietic progenitor cells in blood islands, where ZFAT is exactly expressed. Expression levels of Tal1, Lmo2, and Gata1 in Zfat -/- yolk sacs are much reduced compared with those of wild-type mice, and ChIP-PCR analysis revealed that ZFAT binds promoter regions for these genes in vivo. Furthermore, profound reduction in TAL1, LMO2, and GATA1 protein expressions are observed in Zfat-/- blood islands. Taken together, these results suggest that ZFAT is indispensable for mouse embryonic development and functions as a critical transcription factor for primitive hematopoiesis through direct-regulation of Tal1, Lmo2, and Gata1. Elucidation of ZFAT functions in hematopoiesis might lead to a better understanding of transcriptional networks in differentiation and cellular programs of hematopoietic lineage and provide useful information for applied medicine in stem cell therapy.

Original languageEnglish
Pages (from-to)14199-14204
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number32
DOIs
Publication statusPublished - Aug 10 2010

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Zinc Fingers
AT-Hook Motifs
Hematopoiesis
Yolk Sac
Hemangioblasts
Transcription Factors
Primitive Streak
Genes
Gene Regulatory Networks
Disease Susceptibility
Thyroid Diseases
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Genetic Promoter Regions
Autoimmune Diseases
Embryonic Development
Blood Vessels
Stem Cells
Medicine
Apoptosis

All Science Journal Classification (ASJC) codes

  • General

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Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands. / Tsunoda, Toshiyuki; Takashima, Yasuo; Tanaka, Yoko; Fujimoto, Takahiro; Doi, Keiko; Hirose, Yumiko; Koyanagi, Midori; Yoshida, Yasuhiro; Okamura, Tadashi; Kuroki, Masahide; Sasazuki, Takehiko; Shirasawa, Senji.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 32, 10.08.2010, p. 14199-14204.

Research output: Contribution to journalArticle

Tsunoda, T, Takashima, Y, Tanaka, Y, Fujimoto, T, Doi, K, Hirose, Y, Koyanagi, M, Yoshida, Y, Okamura, T, Kuroki, M, Sasazuki, T & Shirasawa, S 2010, 'Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 32, pp. 14199-14204. https://doi.org/10.1073/pnas.1002494107
Tsunoda, Toshiyuki ; Takashima, Yasuo ; Tanaka, Yoko ; Fujimoto, Takahiro ; Doi, Keiko ; Hirose, Yumiko ; Koyanagi, Midori ; Yoshida, Yasuhiro ; Okamura, Tadashi ; Kuroki, Masahide ; Sasazuki, Takehiko ; Shirasawa, Senji. / Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 32. pp. 14199-14204.
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AU - Fujimoto, Takahiro

AU - Doi, Keiko

AU - Hirose, Yumiko

AU - Koyanagi, Midori

AU - Yoshida, Yasuhiro

AU - Okamura, Tadashi

AU - Kuroki, Masahide

AU - Sasazuki, Takehiko

AU - Shirasawa, Senji

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