Nlrp3 activation in the intestinal epithelium protects against a mucosal pathogen. NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen. Diversity and plasticity in Rab GTPase nucleotide release mechanism has consequences for Rab activation and inactivation.
Share your family tree and photos with the people you know and love Here, the authors demonstrate Src-dependent control of cell size and autophagy through disruption of the Rag GTPaseâ€“GATOR1 complex and mTORC1 activation at the lysosomal surface. Here, the authors show that lysosomal protease deficiency or substrate overload induces lysosomal stress leading to activation of a STAT3-dependent, TFEB-independent pathway of lysosomal hydrolase expression. Most approaches to control gene expression in vivo require generation of knock-in mouse lines and often lack spatiotemporal control. Insets highlight RAB26 (green, filled white arrowhead) and mitochondria (purple, open white arrowhead) interactions (time stamps of images from supplementary material Movie 2 are shown.
BRD4 occupancy at GATA1 OS was substantial in the absence of GATA1, and BRD4 signal increased somewhat at these sites following GATA1 activation. In contrast, BRD3 occupancy increased dramatically at both GATA1-bound promoters and enhancers upon GATA1 activation. Keller, Yong Cheng, Deepti Jain, Axel Visel, Len Pennacchio, Mitchell Weiss, G.A.B., and R.C.H., manuscript submitted January 23, 2015), BRD4 occupancy correlated strongly with H3K27ac in the vicinity of GATA1 OS (supplemental Figure 3B). By this definition, BRD3 was present at 74% of GATA1 sites, BRD4 at 53%, and BRD2 at 27%.
Red dotted line shows no change in mRNA levels with JQ1 treatment. (C) Boxplot showing relationship of activation by GATA1 with JQ1 sensitivity.
Consistent with phenotypic results, BRD3 overexpression also rescued BRD2 deficiency at most, but not all, genes examined (Figure 6C, supplemental Figure 10B). Retroviral BRD2 expression restored this defect, confirming specificity of BRD2 gene targeting. As expected, BRD3 knockdown on its own had no significant impact on gene activation.
Remarks: (1) In the context of abstract convex sets, the maximal tensor product (more usually called the injective tensor product) seems first to have been discussed by Namioka and Phelps ; see also Wittstock For Banach lattices X and Y, let X (circle times) over cap Y-vertical bar pi vertical bar and X circle times Y-vertical bar epsilon vertical bar denote the positive projective and injective tensor products of X and Y, respectively. Some geometric properties inherited by the positive tensor products of atomic Banach lattices or see [14, section 3.8]), called the positive injective tensor product of X and Y .
Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Together with the ability of Brd3 overexpression to rescue BRD2 deficiency, it is possible that phenotypic differences between these proteins may be at least partially due to different expression levels.
(A-C) Microarray expression profiles of G1E cells Â± GATA1 induction in the presence or absence of JQ1. Following GATA1 addition, 5094 transcripts decreased whereas only 220 increased using stringent differential expression criteria (twofold change and Bonferroni-corrected, P < .05)="" (supplemental="" figure="" 4a).="" we="" subsequently="" divided="" bet="" binding="" at="" gata1="" sites="" as="" binding="" at="" candidate="" enhancers="" and="" promoters="" (figure="" 1c).="" gata1="" os="" with="" high="" h3k27ac="" were="" more="" likely="" to="" be="" at="" gene="" promoters="" and="" more="" likely="" to="" be="" co-occupied="" by="" tal1="" (supplemental="" figure="">
BRD4 coordinates recruitment of pause release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon-stimulated genes. Bromodomain and extra-terminal (BET) bromodomain inhibition activate transcription via transient release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein. Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting. Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes.
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To this end, we used shRNAs to deplete BRD3 in BRD2-replete and BRD2-deficient cells (Figure 6A, supplemental Figure 10A). These results suggest BRD2 and BRD4 are individually required for normal GATA1-mediated transcriptional activation. As BRD3 occupies nearly all GATA1 OSs, we had speculated that it was the most relevant BET in GATA1-mediated transcription. In contrast, transcription of other genes like Hba-a1 (Î±-globin) and Uros (involved in heme synthesis) were unperturbed by short-term JQ1 treatment despite their sensitivity to long-term JQ1 exposure and proximity to BET-bound regulatory elements. Indeed, JQ1 treatment of 1 hour removed BETs from all sites examined with relatively little effect on GATA1 occupancy (Figure 4A, supplemental Figure 9A).