Factorbook: an Updated Catalog of Transcription Factor Motifs and Candidate Regulatory Motif Sites

ABSTRACTThe human genome contains roughly 1,600 transcription factors (TFs) (1), DNA-binding proteins recognizing characteristic sequence motifs to exert regulatory effects on gene expression. The binding specificities of these factors have been profiled both in vitro, using techniques such as HT-SELEX (2), and in vivo, using techniques including ChIP-seq (3, 4). We previously developed Factorbook, a TF-centric database of annotations, motifs, and integrative analyses based on ChIP-seq data from Phase II of the ENCODE Project. Here we present an update to Factorbook which significantly expands the breadth of cell type and TF coverage. The update includes an expanded motif catalog derived from thousands of ENCODE Phase II and III ChIP-seq experiments and HT-SELEX experiments; this motif catalog is integrated with the ENCODE registry of candidate cis-regulatory elements to annotate a comprehensive collection of genome-wide candidate TF binding sites. The database also offers novel tools for applying the motif models within machine learning frameworks and using these models for integrative analysis, including annotation of variants and disease and trait heritability. We will continue to expand the resource as ENCODE Phase IV data are released.

Accurate prediction of cis-regulatory modules reveals a prevalent regulatory genome of humans

cis-regulatory modules(CRMs) formed by clusters of transcription factor (TF) binding sites (TFBSs) are as important as coding sequences in specifying phenotypes of humans. It is essential to categorize all CRMs and constituent TFBSs in the genome. In contrast to most existing methods that predict CRMs in specific cell types using epigenetic marks, we predict a largely cell type agonistic but more comprehensive map of CRMs and constituent TFBSs in the gnome by integrating all available TF ChIP-seq datasets. Our method is able to partition 77.47% of genome regions covered by available 6092 datasets into a CRM candidate (CRMC) set (56.84%) and a non-CRMC set (43.16%). Intriguingly, the predicted CRMCs are under strong evolutionary constraints, while the non-CRMCs are largely selectively neutral, strongly suggesting that the CRMCs are likely cis-regulatory, while the non-CRMCs are not. Our predicted CRMs are under stronger evolutionary constraints than three state-of-the-art predictions (GeneHancer, EnhancerAtlas and ENCODE phase 3) and substantially outperform them for recalling VISTA enhancers and non-coding ClinVar variants. We estimated that the human genome might encode about 1.47M CRMs and 68M TFBSs, comprising about 55% and 22% of the genome, respectively; for both of which, we predicted 80%. Therefore, the cis-regulatory genome appears to be more prevalent than originally thought.

Accurate prediction of cis-regulatory modules reveals a prevalent regulatory genome of humans

Annotating all cis-regulatory modules (CRMs) and transcription factor (TF) binding sites(TFBSs) in genomes remains challenging. We tackled the task by integrating putative TFBSs motifs found in available 6,092 datasets covering 77.47% of the human genome. This approach enabled us to partition the covered genome regions into a CRM candidate (CRMC) set (56.84%) and a non-CRMC set (43.16%). Intriguingly, like known enhancers, the predicted 1,404,973 CRMCs are under strong evolutionary constraints, suggesting that they might be cis-regulator. In contrast, the non-CRMCs are largely selectively neutral, suggesting that they might not be cis-regulatory. Our method substantially outperforms three state-of-the-art methods (GeneHancers, EnhancerAtlas and ENCODE phase 3) for recalling VISTA enhancers and ClinVar variants, as well as by measurements of evolutionary constraints. We estimated that the human genome might encode about 1.46 million CRMs and 67 million TFBSs, comprising about 55% and 22% of the genome, respectively; for both of which, we predicted 80%. Therefore, the cis-regulatory genome appears to be more prevalent than originally thought.

Phase-variable bacterial loci: how bacteria gamble to maximise fitness in changing environments

Phase-variation of genes is defined as the rapid and reversible switching of expression — either ON-OFF switching or the expression of multiple allelic variants. Switching of expression can be achieved by a number of different mechanisms. Phase-variable genes typically encode bacterial surface structures, such as adhesins, pili, and lipooligosaccharide, and provide an extra contingency strategy in small-genome pathogens that may lack the plethora of ‘sense-and-respond’ gene regulation systems found in other organisms. Many bacterial pathogens also encode phase-variable DNA methyltransferases that control the expression of multiple genes in systems called phasevarions (phase-variable regulons). The presence of phase-variable genes allows a population of bacteria to generate a number of phenotypic variants, some of which may be better suited to either colonising certain host niches, surviving a particular environmental condition and/or evading an immune response. The presence of phase-variable genes complicates the determination of an organism's stably expressed antigenic repertoire; many phase-variable genes are highly immunogenic, and so would be ideal vaccine candidates, but unstable expression due to phase-variation may allow vaccine escape. This review will summarise our current understanding of phase-variable genes that switch expression by a variety of mechanisms, and describe their role in disease and pathobiology.

Temporospatial Characterization of Brain Oscillations (TSCBO) Associated with Subprocesses of Verbal Working Memory in Schizophrenia

The studies of the neural correlates of verbal working memory in schizophrenia are somewhat inconsistent. This could be related to experimental paradigms that engage differentially working memory components or methodological limitations in terms of characterization of brain activity. Magnetoencephalographic recordings were obtained on 10 schizophrenia patients and 11 healthy controls while performing a modified Sternberg paradigm to investigate subprocesses of verbal working memory. A new method for temporospatial characterization of brain oscillations was applied to whole head recordings and a 1–48 Hz frequency range. Patients differed from controls in event-related synchronization/desynchronization (ERS/ERD) patterns during the encode phase, the mid-maintain phase, and the end of the maintain phase. During the encode phase, patients did not show 1–4 Hz ERS in the left anterior frontal and left parietal lobes. In the mid-maintain phase, the left anterior frontal and left parietal lobes 1–4 Hz ERS, and the bilateral occipital lobes 8–32 Hz ERS were not observed in patients. At the end of the maintain phase, patients did not exhibit 12–48 Hz ERD in the left frontal and parietal lobes. The behavioral data showed reduced primacy effect In schizophrenia, the encode and maintain subprocesses were associated with less ERS and less ERD, respectively. These ERS/ERD abnormalities had specificity in terms of frequency and spatial location. Less ERD reflects reduced complexity of the neural activity, while reduced ERS reflects failure of the neural systems to resume idle state. The impaired primacy effect appears related to specific ERS/ERD patterns in the encode and maintain phases.