A new model for long-range chromatin reorganization linked to enhancer activation [Agilent_RNA]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE89515 | GEO | 2016/11/04
SECONDARY ACCESSION(S): PRJNA352421
REPOSITORIES: GEO
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Project description:The most prominent model for long-range enhancer regulation involves direct enhancer-promoter interaction by looping out the intervening chromatin. Using a synthetic biology approach, we have determined that a chromatin unfolding bteween Shh and its enhancers is regulated specifically by the Shh-Brain-Enhancers and is mediated by the recruitment of Poly (ADP-Ribose) Polymerase 1. This ‘chromatin unfolding’ model represents a new mechanism of long-range enhancer-promoter communication in addition to the looping and tracking models. ChIP-on-chip for H3K27me3 on the Shh regulatory region on ESCs and transfected ESCs and NPC showed no loss of Polycomb marks upon Shh activation.
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Project description:The most prominent model for long-range enhancer regulation involves direct enhancer-promoter interaction by looping out the intervening chromatin. Using a synthetic biology approach, we have determined that a chromatin unfolding between Shh and its enhancers is regulated specifically by the Shh-Brain-Enhancers and is mediated by the recruitment of Poly (ADP-Ribose) Polymerase 1. This ‘chromatin unfolding’ model represents a new mechanism of long-range enhancer-promoter communication in addition to the looping and tracking models. ChIP-on-chip for H3K27me3 and H3K27ac on the Shh regulatory region on ESCs and transfected ESCs showed a gain of H3k27ac specifically on active enhancers and no loss of Polycomb marks upon Shh activation.
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Project description:The most prominent model for long-range enhancer regulation involves direct enhancer-promoter interaction by looping out the intervening chromatin. Using a synthetic biology approach, we have determined that a chromatin unfolding bteween Shh and its enhancers is regulated specifically by the Shh-Brain-Enhancers and is mediated by the recruitment of Poly (ADP-Ribose) Polymerase 1. This ‘chromatin unfolding’ model represents a new mechanism of long-range enhancer-promoter communication in addition to the looping and tracking models. Using 5C study the enhancer-driven activation of the Sonic hedgehog gene (Shh)
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Project description:Limb-specific expression of Shh is regulated by the long-range (~one megabasepair distant) ZRS enhancer. In the mouse, murine limb bud restricted spatiotemporal expression of Shh occurs from ~E10 until E11.5 at the distal posterior margin is essential for the correct formation of the autopod. Here, we have analyzed the higher-order chromatin conformation of Shh in expressing and non-expressing tissues, both by fluorescence in situ hybridization (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequences of Shh/ZRS co-localization only in the Shh expressing regions of the limb bud consistent with the formation of an enhancer-promoter loop. However, Shh-ZRS spatial distances were consistently shorter than intervening distances to a neural enhancer in all tissues and developmental stages analyzed – regardless of Shh expression. 5C also identified a topologically associating domain (TAD) over the Shh-ZRS genomic region and enriched interactions between Shh and ZRS, but in the head, body and limb buds of E11.5 embryos, so also not linked to Shh expression. We show that gene-enhancer (Shh/ZRS) co-localization correlates with the spatiotemporal domain of limb bud-specific Shh expression, but that close Shh/ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigate Shh expression.
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Project description:Many questions remain about how close association of genes and distant enhancers occurs and how this is linked to transcription activation. In erythroid cells, LDB1 is recruited to the β-globin locus via LMO2 and is required for looping of the β-globin locus control region (LCR) to the active β-globin promoter. We show that the LDB1 dimerization domain (DD) is necessary and, when fused to LMO2 is sufficient, to completely restore LCR-promoter looping and transcription in LDB1 depleted cells. The looping function of the DD is unique and irreplaceable by heterologous dimerization domains. Dissection of the DD revealed distinct functional properties of conserved subdomains. Notably, a conserved helical region (DD4/5) is dispensable for LDB1 dimerization and chromatin looping but essential for transcriptional activation. DD4/5 is required for the recruitment of the co-regulators FOG1 and NuRD complex. Lack of DD4/5 alters histone acetylation and RNA polymerase II recruitment and results in failure of the locus to migrate to the nuclear interior as normally occurs during erythroid maturation. These results uncouple enhancer-promoter looping from nuclear migration and transcription activation and reveal new roles for LDB1in these processes. RNA-seq in LDB1 knockdown, LDB1 delta4/5 construct, LDB1 full-length construct, and control in induced MEL cells; three replicates each.
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Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs Enhancer usually regulates its targets through physical contact/interaction. In order to study chromosome conformation of Myc locus and potential distal enhancer E1-E5 region in murine AML cells, we utilize the high resolution 4C-seq and analysis pipeline to search cis elements that physical interact with Myc and E1-E5 region through setting up two individual viewpoints in these two regions.
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Project description:Enhancers play key roles in gene regulation. However, comprehensive enhancer discovery is challenging because most enhancers, especially those affected in complex diseases, have weak effects on gene expression. Through gene regulatory network modeling, we identified that dynamic cell state transitions, a critical missing component in prevalent enhancer discovery strategies, can be utilized to improve the cells’ sensitivity to enhancer perturbation. Guided by the modeling results, we performed a mid-transition CRISPRi-based enhancer screen utilizing human embryonic stem cell definitive endoderm differentiation as a dynamic transition system. The screen discovered a comprehensive set of enhancers (4 to 9 per locus) for each of the core lineage-specifying transcription factors (TFs), including many enhancers with weak to moderate effects. Integrating the screening results with enhancer activity measurements (ATAC-seq, H3K27ac ChIP-seq) and three-dimensional enhancer-promoter interaction information (CTCF looping, Hi-C), we were able to develop a CTCF loop-constrained Interaction Activity (CIA) model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Together, our dynamic network-guided enhancer screen and the CIA enhancer prediction model provide generalizable strategies for sensitive and more comprehensive enhancer discovery in both normal and pathological cell state transitions.
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