ChromNet: Learning the human chromatin network from all ENCODE ChIP-seq data

Lundberg, Scott; Tu, William B.; Raught, Brian; Penn, Linda Z.; Hoffman, Michael M.; Lee, Su-In

doi:10.1186/s13059-016-0925-0

Cited by 32 publications

(30 citation statements)

References 64 publications

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“…Not surprisingly, associated proteins (including the cohesin complex in mammals [88-90] mediate architectural functions, while other sequence-specific factors, notably ZNF143 [91-93], may help target CTCF to a subset of its genomic sites. In addition, tRNA genes and their associated factors (which include TFIIIC and CTCF) act as boundaries and affect chromosome organization [94].…”

Section: Orientation Dependence and Loop Topologymentioning

confidence: 99%

“…While a number of direct DNA binding proteins contribute to boundary function in flies, only one, CTCF, has been strongly correlated with boundaries so far in mammals [29,31]. Not surprisingly, associated proteins (including the cohesin complex in mammals [88][89][90]) mediate architectural functions, while other sequence-specific factors, notably ZNF143 [91][92][93], may help target CTCF to a subset of its genomic sites. In addition, tRNA genes and their associated factors (which include TFIIIC and CTCF) act as boundaries and affect chromosome organization [94].…”

Section: Mammalian Boundariesmentioning

confidence: 99%

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Boundaries of loop domains (insulators): Determinants of chromosome form and function in multicellular eukaryotes

et al. 2017

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Summary Chromosomes in multicellular animals are subdivided into a series of looped domains. In addition to being the underlying principle for organizing the chromatin fiber, looping is critical for processes ranging from gene regulation to recombination and repair. The subdivision of chromosomes into looped domains depends upon a special class of architectural elements called boundaries or insulators. These elements are distributed throughout the genome and are ubiquitous building blocks of chromosomes. In this review, we focus on features of boundaries that are critical in determining the topology of the looped domains and their genetic properties. We highlight the properties of fly boundaries that are likely to have an important bearing on the organization of looped domains in vertebrates, and discuss the functional consequences of the observed similarities and differences.

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Section: Orientation Dependence and Loop Topologymentioning

confidence: 99%

Section: Mammalian Boundariesmentioning

confidence: 99%

Boundaries of loop domains (insulators): Determinants of chromosome form and function in multicellular eukaryotes

et al. 2017

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“…In that context, epigenetics clearly plays a central role as it influences the binding of the regulators and ultimately gene expression [ 14 ]. Provided the variety of regulatory mechanisms, deciphering their combination requires mathematical/computational methods able to consider all possible combinations [ 15 ]. Several methods have recently been proposed to tackle this problem [ 16 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

Probing instructions for expression regulation in gene nucleotide compositions

et al. 2018

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Gene expression is orchestrated by distinct regulatory regions to ensure a wide variety of cell types and functions. A challenge is to identify which regulatory regions are active, what are their associated features and how they work together in each cell type. Several approaches have tackled this problem by modeling gene expression based on epigenetic marks, with the ultimate goal of identifying driving regions and associated genomic variations that are clinically relevant in particular in precision medicine. However, these models rely on experimental data, which are limited to specific samples (even often to cell lines) and cannot be generated for all regulators and all patients. In addition, we show here that, although these approaches are accurate in predicting gene expression, inference of TF combinations from this type of models is not straightforward. Furthermore these methods are not designed to capture regulation instructions present at the sequence level, before the binding of regulators or the opening of the chromatin. Here, we probe sequence-level instructions for gene expression and develop a method to explain mRNA levels based solely on nucleotide features. Our method positions nucleotide composition as a critical component of gene expression. Moreover, our approach, able to rank regulatory regions according to their contribution, unveils a strong influence of the gene body sequence, in particular introns. We further provide evidence that the contribution of nucleotide content can be linked to co-regulations associated with genome 3D architecture and to associations of genes within topologically associated domains.

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“…There is little doubt that dysregulation of neuronal gene expression in prefrontal cortex (PFC) and other areas of the cerebral cortex regions implicated in the neural circuitry of psychosis (reviewed in Lewis & Sweet, ) contributes to the pathophysiology of SCZ, broadly affecting excitatory and inhibitory neurotransmission, metabolism, myelination, and immune signaling (Arion et al, ; Horvath & Mirnics, ; Middleton, Mirnics, Pierri, Lewis, & Levitt, ; Mirnics, Middleton, Marquez, Lewis, & Levitt, ; Vawter et al, ; Volk et al, ; Zhao et al, ). With the transcriptional process intimately connected to chromatin structure, and function in human cells and model organisms alike (Brown & Celniker, ; Lundberg et al, ), one would therefore expect that epigenomic markers associated with open (“active,” “loose”) chromatin permissive for gene expression, versus repressed, and silenced chromatin, will show significant alterations in brain tissue from subjects diagnosed with SCZ. Such type of epigenomic explorations in SCZ postmortem brain initially focused on DNA methylation, one of the key epigenetic mechanisms involved in the regulation of gene expression (Klose & Bird, ).…”

Section: Dna Methylation and Other Epigenomic Alterations In Schizophmentioning

confidence: 99%

The epigenomics of schizophrenia, in the mouse

Javidfar¹,

Park²,

Kassim³

et al. 2017

American J of Med Genetics Pt B

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Large-scale consortia including the Psychiatric Genomics Consortium, the Common Minds Consortium, BrainSeq and PsychENCODE, and many other studies taken together provide increasingly detailed insights into the genetic and epigenetic risk architectures of schizophrenia and offer vast amounts of molecular information, but with largely unexplored therapeutic potential. Here we discuss how epigenomic studies in human brain could guide animal work to test the impact of disease-associated alterations in chromatin structure and function on cognition and behavior. For example, transcription factors such as MYOCYTE-SPECIFIC ENHANCER FACTOR (MEF2C), or multiple regulators of the open chromatin mark, methyl-histone H3-lysine 4, are associated with the genetic risk architectures of common psychiatric disease and alterations in chromatin structure and function in diseased brain tissue. Importantly, these molecules also affect cognition and behavior in genetically engineered mice, including virus-mediated expression changes in prefrontal cortex and other key nodes in the circuitry underlying psychosis. Therefore, preclinical and small laboratory animal work could target genomic sequences affected by chromatin alterations in schizophrenia. To this end, in vivo editing of enhancer and other regulatory non-coding DNA by RNA-guided nucleases including CRISPR-Cas, and designer transcription factors, could be expected to deliver pipelines for novel therapeutic approaches aimed at improving cognitive dysfunction and other core symptoms of schizophrenia.

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ChromNet: Learning the human chromatin network from all ENCODE ChIP-seq data

Cited by 32 publications

References 64 publications

Boundaries of loop domains (insulators): Determinants of chromosome form and function in multicellular eukaryotes

Boundaries of loop domains (insulators): Determinants of chromosome form and function in multicellular eukaryotes

Probing instructions for expression regulation in gene nucleotide compositions

The epigenomics of schizophrenia, in the mouse

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