Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs during Differentiation and Regeneration

Abstract

Summary BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic lineages following acute injury depends on the activation of each of these signaling pathways to induce expression of key blood genes. Both SMAD1 and TCF7L2 co-occupy sites with master regulators adjacent to hematopoietic genes. In addition, both SMAD1 and TCF7L2 follow the binding of the predominant lineage regulator during differentiation from multipotent hematopoietic progenitor cells to erythroid cells. Furthermore, induction of the myeloid lineage regulator C/EBPα in erythroid cells shifts binding of SMAD1 to sites newly occupied by C/EBPα, while expression of the erythroid regulator GATA1 directs SMAD1 loss on non-erythroid targets. We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control the gene programs defining cellular identity.

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

“…To further validate miR-199a-5p as a regulator of the WNT signaling pathway, we measured the levels of several well-characterized WNT/b-catenin-downstream target genes axin2, myca (zebrafish c-myc ortholog), and ccnd1 (cyclin D1) in the Tg(mylz2-miR-199a-5p) zebrafish and primary MB overexpressing miR-199a-5p lentivirus. 39 The levels of these miR-199a-5p target genes were significantly reduced in miR-199a-5p overexpressing zebrafish compared with wild-type controls (Figures 7f and g). These results suggest that high levels of miR-199a-5p inhibit WNT signaling, which drives myoblast proliferation and differentiation.…”

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

“…Chromatin profilings of LEF/TCF proteins in different cell lines and/or in vivo tissues point to the view that their target genes and cooperative regulators are dependent on cell type and context. This is perhaps best exemplified by the finding that following acute injury, Wnt-induced hematopoietic cells of the erythroid lineage guide nuclear TCF4 to regulatory sites of key blood genes that are already bound by GATA2 (Trompouki et al 2011). In contrast, in neonatal and adult livers, TCF4 plays an essential role in regulating the constellation of genes that govern metabolism, and here the metabolic genes show co-occupancy of TCF4 and the liver transcription factor CDX2 (Verzi et al 2010).…”

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

“…We then conducted a bioinformatics-based screen using microarray data on CREB overexpression and CREB chromatin immunoprecipitation-sequencing (ChIP-Seq) data using data available at Encyclopedia of DNA Elements (ENCODE) and elsewhere to identify regulators of CREB function in hematopoietic cells (Esparza et al, 2008;Jolma et al, 2010;Pencovich et al, 2011;Raney et al, 2011;Trompouki et al, 2011;Martens et al, 2012). Using insight gained from bioinformatics, we discover that the bone morphogenetic protein (BMP) signaling pathway acts downstream of PKA-CREB signaling in regulating AGM hematopoiesis.…”