Papers on transcription factor binding #TFbinding. Maintained by @TeifLab. Also see @nucleosome_bot, @CTCF_papers, @DNAbinding, @cfDNA_papers, @generegulation
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ALT We describe an effort ("Codebook") to determine the sequence specificity of 332 putative and largely uncharacterized human transcription factors (TFs), as well as 61 control TFs. Nearly 5,000 independent experiments across multiple in vitro and in vivo assays produced motifs for just over half of the putative TFs analyzed (177, or 53%), of which most are unique to a single TF. The data highlight the extensive contribution of transposable elements to TF evolution, both in cis and trans, and identify tens of thousands of conserved, base-level binding sites in the human genome. The use of multiple assays provides an unprecedented opportunity to benchmark and analyze TF sequence specificity, function, and evolution, as further explored in accompanying manuscripts. 1,421 human TFs are now associated with a DNA binding motif. Extrapolation from the Codebook benchmarking, however, suggests that many of the currently known binding motifs for well-studied TFs may inaccurately describe the TF's
ALT A DNA sequence pattern, or "motif", is an essential representation of DNA-binding specificity of a transcription factor (TF). Any particular motif model has potential flaws due to shortcomings of the underlying experimental data and computational motif discovery algorithm. As a part of the Codebook/GRECO-BIT initiative, here we evaluated at large scale the cross-platform recognition performance of positional weight matrices (PWMs), which remain popular motif models in many practical applications. We applied ten different DNA motif discovery tools to generate PWMs from the "Codebook" data comprised of 4,237 experiments from five different platforms profiling the DNA-binding specificity of 394 human proteins, focusing on understudied transcription factors of different structural families. For many of the proteins, there was no prior knowledge of a genuine motif. By benchmarking-supported human curation, we constructed an approved subset of experiments comprising about 30% of all experim.
ALT Most of the human genome is thought to be non-functional, and includes large segments often referred to as "dark matter" DNA. The genome also encodes hundreds of putative and poorly characterized transcription factors (TFs). We determined genomic binding locations of 166 uncharacterized human TFs in living cells. Nearly half of them associated strongly with known regulatory regions such as promoters and enhancers, often at conserved motif matches and co-localizing with each other. Surprisingly, the other half often associated with genomic dark matter, at largely unique sites, via intrinsic sequence recognition. Dozens of these, which we term "Dark TFs", mainly bind within regions of closed chromatin. Dark TF binding sites are enriched for transposable elements, and are rarely under purifying selection. Some Dark TFs are KZNFs, which contain the repressive KRAB domain, but many are not: the Dark TFs also include known or potential pioneer TFs...
ALT The study design and small-scale nucleosome repositioning analysis. A Scheme of the study: paired tumour/normal breast tissues taken from breast cancer patients numbered P1–P4 were used to determine nucleosome positioning using MNase-seq and MNase-assisted histone H3 ChIP-seq (MNase-H3), complemented by whole-genome sequencing of cell-free DNA extracted from blood plasma from the same patients. The analysis of each sample was performed individually, without pooling. B Example genomic region (Chr 17: 7,855,262–7,592,516) enclosing gene TP53 and nucleosome occupancy maps for patient P3. Tracks top to bottom: normal tissue MNase-H3 and MNase-seq; tumour tissue MNase-H3 and MNase-seq; cfDNA in two replicates; UCSC Genome Browser track with ENCODE Factorbook TF motifs. Rectangles show regions containing common (brown), gained (green) and shifted nucleosomes (violet). The gained and shifted classifications are not mutually exclusive. C Fold enrichment of nucleosomes that were gained and lost
ALT Nucleosome repeat length shortening in cancer. A Frequencies of distances between dyads of DNA fragments protected from MNase digestion in paired normal and tumour breast tissue samples from patient P2. B Genome-wide NRL values calculated for each sample reported in this study. The difference of NRLs between normal and tumour tissues is statistically significant (p = 0.014, paired sample t test). Open squares—average values across all samples in a given condition; horizontal lines—median values for a given condition. The colours of the points corresponding to NRL values in N/T tissues are assigned per patient and per experiment type as follows: MNase-seq: patient P1 (black), P2 (red), P3 (blue), P4 (green); MNase-assisted H3 ChIP-seq: patient P1 (violet), P3 (brown), P4 (cyan). Panels A and B use DNA fragments of sizes 120–180 bp. C NRL in normal (grey violins) and tumour (beige violins) breast tissue calculated inside genomic regions enriched with 160–180 bp DNA fragments (“long nuc”)
![Effects of linker histones on nucleosome repositioning in breast cancer. A Correlation of GC content and H1 occupancy in 10-kb regions genome-wide. H1 variants H1.0, H1.2 and H1.5 preferentially bind AT-rich regions, while H1.4 and H1X have a higher affinity for GC-rich regions. B–D Averaged aggregate profiles of H1 occupancy around different types of DNA fragments protected from MNase digestion. These profiles were first calculated individually for each MNase-seq tumour tissue sample reported in this study, and then averaged across all patients. B Occupancy of H1 variants around nucleosome dyads calculated for different DNA fragment sizes. C H1 occupancy in the region [-50, 50] bp around nucleosome dyad calculated for different H1 variants as a function of DNA fragment size. D Average H1X occupancy in T47D breast cancer cell line calculated around DNA fragments of 160–180 bp in normal (black lines) and tumour breast tissues (red). E Average H1X occupancy profiles...](https://pbs.twimg.com/media/GKK2oq5WoAAD6AP.jpg?name=orig)
ALT Effects of linker histones on nucleosome repositioning in breast cancer. A Correlation of GC content and H1 occupancy in 10-kb regions genome-wide. H1 variants H1.0, H1.2 and H1.5 preferentially bind AT-rich regions, while H1.4 and H1X have a higher affinity for GC-rich regions. B–D Averaged aggregate profiles of H1 occupancy around different types of DNA fragments protected from MNase digestion. These profiles were first calculated individually for each MNase-seq tumour tissue sample reported in this study, and then averaged across all patients. B Occupancy of H1 variants around nucleosome dyads calculated for different DNA fragment sizes. C H1 occupancy in the region [-50, 50] bp around nucleosome dyad calculated for different H1 variants as a function of DNA fragment size. D Average H1X occupancy in T47D breast cancer cell line calculated around DNA fragments of 160–180 bp in normal (black lines) and tumour breast tissues (red). E Average H1X occupancy profiles...
ALT NRL shortening as a novel breast cancer marker. A–E NRL values calculated for each individual sample from this study inside different types of genomic regions. A Transcriptionally active A-compartments of chromatin annotated in breast cancer MCF-7 cells; B Regions surrounding gene promoters. C Genomic regions around Alu repeats; D Regions enriched with H1X linker histones in breast cancer T47D cells; E Differentially methylated DNA regions annotated based on cell lines MCF-10A, MCF-7 and MDA-MB-231. Open squares—average NRL values for a given condition; horizontal lines—median values. The colours of the points are assigned per sample as in Fig. 3A. F A scheme of the global change of nucleosome compaction in breast cancer tissues. DNA (black) is wrapped around histone octamers (grey) in contact with linker histones (blue). MNase used in this study or apoptotic nucleases present in situ (orange) cut DNA not protected by nucleosomes and linker histones. Cancer cells have shorter NRL...
