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Articles by A Dean
Total Records ( 2 ) for A Dean
  H Bhatia , J. L Hallock , A Dutta , S Karkashon , L. S Sterner , T Miyazaki , A Dean and J. A. Little

Short-chain fatty acids (SCFAs; butyrate and propionate) up-regulate embryonic/fetal globin gene expression through unclear mechanisms. In a murine model of definitive erythropoiesis, SCFAs increased embryonic β-type globin gene expression in primary erythroid fetal liver cells (eFLCs) after 72 hours in culture, from 1.7% (± 1.2%) of total β-globin gene expression at day 0 to 4.9% (± 2.2%) in propionate and 5.4% (± 3.4%) in butyrate; this effect was greater in butyrate plus insulin/erythropoietin (BIE), at 19.5% (± 8.3%) compared with 0.1% (± 0.1%) in ins/EPO alone (P < .05). Fetal -globin gene expression was increased in human transgene-containing eFLCs, to 35.9% (± 7.0%) in BIE compared with 4.4% (± 4.2%) in ins/EPO only (P < .05). Embryonic globin gene expression was detectable in 11 of 15 single eFLCs treated with BIE, but in0 of 15 ins/EPO-only treated cells. Butyrate-treated [65.5% (± 9.9%)] and 77.5% (± 4.0%) propionate-treated eFLCs were highly differentiated in culture, compared with 21.5% (± 3.5%) in ins/EPO (P < .005). Importantly, signaling intermediaries, previously implicated in induced embryonic/fetal globin gene expression (STAT5, p42/44, and p38), were not differentially activated by SCFAs in eFLCs; but increased bulk histone (H3) acetylation was seen in SCFA-treated eFLCs. SCFAs induce embryonic globin gene expression in eFLCS, which are a useful short-term and physiologic primary cell model of embryonic/fetal globin gene induction during definitive erythropoiesis.

  L Li , J. Y Lee , J Gross , S. H Song , A Dean and P. E. Love

During erythrocyte development, the nuclear cofactor Lim domain binding protein 1 (Ldb1) functions as a core subunit of multiprotein DNA binding complexes that include the transcription factors Scl and Gata-1 and the Lim-only adapter Lmo2. Scl, Gata-1, and Lmo2 are each required for erythropoiesis, suggesting that Ldb1-nucleated transcription complexes regulate key steps during erythropoiesis. We documented a requirement for Ldb1 in erythropoiesis in mice. Analysis of ldb1–/– embryos revealed a critical requirement for Ldb1 during primitive erythropoiesis, and conditional inactivation of ldb1 at later stages of gestation and in adult mice demonstrated that Ldb1 is continuously required for both definitive erythropoiesis and megakaryopoiesis. Down-regulation of Ldb1 in erythroblasts inhibited the expression of multiple erythroid-specific and prosurvival genes. These results represent the first unequivocal demonstration of a role for Ldb1 in erythropoiesis in vivo and establish a critical function for Ldb1-nucleated complexes in regulating the erythroid/megakaryocyte transcriptional program.

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