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Author(s): Jianxun Wang [1, 2]; Kathleen Scully [1, 6]; Xiaoyan Zhu [1, 6]; Ling Cai [1, 3, 6]; Jie Zhang [1]; Gratien G. Prefontaine [1]; Anna Krones [1]; Kenneth A. [...]

An unexpected strategy for [beta]-catenin-dependent regulation of cell-lineage determination based on interactions between [beta]-catenin and a specific homeodomain factor, Prop1, is presented. A novel transcriptional strategy that underlies [beta]-catenin control of cell-lineage determination in organogenesis is discovered during the study.

Author(s): Xue Li (corresponding author) [1]; Kenneth A. Ohgi [1]; Jie Zhang [1]; Anna Krones [1]; Kevin T. Bush [2]; Christopher K. Glass [3]; Sanjay K. Nigam [2]; Aneel K. [...]

Substantial evidence supports the hypothesis that enhancers are critical regulators of cell-type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of LIM domain-binding protein 1 (LDB1)/cofactor of LIM homeodomain protein 2/nuclear LIMinteractor, interactingwith the enhancer-binding protein achaete-scute complex homolog 1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target genes. Although LDB1-dependent activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of metastasis-associated 1 family, member 2, a component of the nucleosome remodeling deacetylase complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type. [ABSTRACT FROM AUTHOR]

Author(s): Xue Li; Kenneth A. Ohgi; Jie Zhang; Anna Krones; Kevin T. Bush; Christopher K. Glass; Sanjay K. Nigam; Aneel K. Aggarwal; Richard Maas; David W. Rose; Michael G. Rosenfeld [...]

Summary: The association between hyperinflammatory states and numerous diseases is widely recognized, but our understanding of the molecular strategies that have evolved to prevent uncontrolled activation of inflammatory responses remains incomplete. Here, we report a critical, nontranscriptional role of GPS2 as a guardian against hyperstimulation of the TNF-α-induced gene program. GPS2 cytoplasmic actions are required to specifically modulate RIP1 ubiquitylation and JNK activation by inhibiting TRAF2/Ubc13 enzymatic activity. In vivo relevance of GPS2 anti-inflammatory role is confirmed by inhibition of TNF-α target genes in macrophages and by improved insulin signaling in the adipose tissue of aP2-GPS2 transgenic mice. As the nontranscriptional role is complemented by GPS2 functioning as positive and negative cofactor for nuclear receptors, in vivo overexpression also results in elevated circulating level of Resistin and development of hepatic steatosis. Together, these studies define GPS2 as a molecular guardian required for precise control of inflammatory responses involved in immunity and homeostasis. [ABSTRACT FROM AUTHOR]

Enhancers have been functionally described for >35 years, but the molecular principles underlying the integration of regulatory inputs to alternate gene enhancers used during mammalian organogenesis remain incompletely understood. Using a combination of in vivo enhancer mapping and proteomics approaches, we have established that two distant and distinct early enhancers, each requiring different transcription complexes, are required for full activation of the gene encoding the pituitary lineage determining factor, Pit1. A transcription factor belonging to the "giant, multiple-homeodomain and zinc finger family." Atbf1, serves as a novel pituitary regulator for one of the two required enhancers as shown by genetic and in vitro analysis. Enhancers have been functionally described for >35 years, but the molecular principles underlying the integration of regulatory inputs to alternate gene enhancers used during mammalian organogenesis remain incompletely understood. Using a combination of in vivo enhancer mapping and proteomics approaches, we have established that two distant and distinct early enhancers, each requiring different transcription complexes, are required for full activation of the gene encoding the pituitary lineage determining factor, Pit1. A transcription factor belonging to the "giant, multiple-homeodomain and zinc finger family." Atbf1, serves as a novel pituitary regulator for one of the two required enhancers as shown by genetic and in vitro analysis. [ABSTRACT FROM AUTHOR]

The precise mechanistic relationship between gene activation and repression events is a central question in mammalian organogenesis, as exemplified by the evolutionarily conserved sine oculis (Six), eyes absent (Eya) and dachshund (Dach) network of genetically interacting proteins. Here, we report that Six1 is required for the development of murine kidney, muscle and inner ear, and that it exhibits synergistic genetic interactions with Eya factors. We demonstrate that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signalling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, causing transcriptional activation through recruitment of co-activators. The gene-specific recruitment of a co-activator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis. [ABSTRACT FROM AUTHOR]

LIM domains are required for both inhibitory effects on LIM homeodomain transcription factors and synergistic transcriptional activation events. The inhibitory actions of the LIM domain can often be overcome by the LIM co-regulator known as CLIM2, LDB1 and NLI (referred to hereafter as CLIM2; refs 2-4). The association of the CLIM cofactors with LIM domains does not, however, improve the DNA-binding ability of LIM homeodomain proteins, suggesting the action of a LIM-associated inhibitor factor. Here we present evidence that LIM domains are capable of binding a novel RING-H2 zinc-finger protein, Rlim (for RING finger LIM domain-binding protein), which acts as a negative co-regulator via the recruitment of the Sin3A/histone deacetylase corepressor complex. A corepressor function of RLIM is also suggested by in vivo studies of chick wing development. Overexpression of the gene Rnf12, encoding Rlim, results in phenotypes similar to those observed after inhibition of the LIM homeodomain factor LHX2, which is required for the formation of distal structures along the proximodistal axis, or by overexpression of dominant-negative CLIM1. We conclude that Rlim is a novel corepressor that recruits histone deacetylase-containing complexes to the LIM domain. [ABSTRACT FROM AUTHOR]

Presents a correction to the article "Eya Protein Phosphatase Activity Regulates Six1-Dach-Eya Transcriptional Effects in Mammalian Organogenesis," that was previously published in the 2003 issue of the periodical "Nature."

Investigates the defect in the histone acetyltransferase activity of the nuclear transcriptional coactivator CREB-binding protein (CBP) in Rubinstein-Taybi syndrome (RTS). Identification of microdeletion in one RTS patient using fluorescent in situ hybridization analysis; Heteroallelic mutations; Introduction of missense mutation to recombinant mouse CBP.

Summary Enhancers provide critical information directing cell-type-specific transcriptional programs, regulated by binding of signal-dependent transcription factors and their associated cofactors. Here, we report that the most strongly activated estrogen (E 2 )-responsive enhancers are characterized by trans -recruitment and in situ assembly of a large 1–2 MDa complex of diverse DNA-binding transcription factors by ERα at ERE-containing enhancers. We refer to enhancers recruiting these factors as mega transcription factor-bound in trans (MegaTrans) enhancers. The MegaTrans complex is a signature of the most potent functional enhancers and is required for activation of enhancer RNA transcription and recruitment of coactivators, including p300 and Med1. The MegaTrans complex functions, in part, by recruiting specific enzymatic machinery, exemplified by DNA-dependent protein kinase. Thus, MegaTrans-containing enhancers represent a cohort of functional enhancers that mediate a broad and important transcriptional program and provide a molecular explanation for transcription factor clustering and hotspots noted in the genome. [ABSTRACT FROM AUTHOR]

Summary: While the biological roles of canonical Wnt/β-catenin signaling in development and disease are well documented, understanding the molecular logic underlying the functionally distinct nuclear transcriptional programs mediating the diverse functions of β-catenin remains a major challenge. Here, we report an unexpected strategy for β-catenin-dependent regulation of cell-lineage determination based on interactions between β-catenin and a specific homeodomain factor, Prop1, rather than Lef/Tcfs. β-catenin acts as a binary switch to simultaneously activate expression of the critical lineage-determining transcription factor, Pit1, and to repress the gene encoding the lineage-inhibiting transcription factor, Hesx1, acting via TLE/Reptin/HDAC1 corepressor complexes. The strategy of functionally distinct actions of a homeodomain factor in response to Wnt signaling is suggested to be prototypic of a widely used mechanism for generating diverse cell types from pluripotent precursor cells in response to common signaling pathways during organogenesis. [Copyright &y& Elsevier]