Joint sequence and chromatin neural networks characterize the differential abilities of Forkhead transcription factors to engage inaccessible chromatin
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE244411 | GEO | 2023/10/04
REPOSITORIES: GEO
Similar Datasets
Project description:The DNA-binding activities of transcription factors (TFs) are influenced by both intrinsic sequence preferences and extrinsic interactions with cell-specific chromatin landscapes and other regulatory proteins. Disentangling the roles of these determinants in TF-DNA binding remains challenging. For instance, the FoxA subfamily of Forkhead domain TFs are known pioneer factors, yet their binding varies across cell types, pointing to a combination of intrinsic and extrinsic forces guiding their binding. How such sequence and chromatin influences vary across related Forkhead domain TFs remains mostly uncharacterized. Here, we present a principled approach to compare the relative contributions of intrinsic DNA sequence preference and cell-specific chromatin environments to a TF’s DNA-binding activities. We over-express a selection of Fox TFs in mouse embryonic stem (mES) cells, which offer a platform to contrast each TF's binding activity within the same preexisting chromatin background. By developing and applying a neural network that jointly models sequence and chromatin data, we can evaluate how sequence and preexisting chromatin features contribute to induced TF binding, both at individual sites and genome-wide. We demonstrate that Fox TFs bind different DNA targets, and drive differential gene expression patterns, even when induced in identical chromatin settings. Differential Fox binding activities can be attributed to distinct DNA-binding preferences coupled with differential abilities to engage relatively inaccessible chromatin. We propose that varying preferences for preexisting chromatin states enables the functional diversification of paralogous TFs.
2023-10-04 | GSE244410 | GEO
Project description:The DNA-binding activities of transcription factors (TFs) are influenced by both intrinsic sequence preferences and extrinsic interactions with cell-specific chromatin landscapes and other regulatory proteins. Disentangling the roles of these determinants in TF-DNA binding remains challenging. For instance, the FoxA subfamily of Forkhead domain TFs are known pioneer factors, yet their binding varies across cell types, pointing to a combination of intrinsic and extrinsic forces guiding their binding. How such sequence and chromatin influences vary across related Forkhead domain TFs remains mostly uncharacterized. Here, we present a principled approach to compare the relative contributions of intrinsic DNA sequence preference and cell-specific chromatin environments to a TF’s DNA-binding activities. We over-express a selection of Fox TFs in mouse embryonic stem (mES) cells, which offer a platform to contrast each TF's binding activity within the same preexisting chromatin background. By developing and applying a neural network that jointly models sequence and chromatin data, we can evaluate how sequence and preexisting chromatin features contribute to induced TF binding, both at individual sites and genome-wide. We demonstrate that Fox TFs bind different DNA targets, and drive differential gene expression patterns, even when induced in identical chromatin settings. Differential Fox binding activities can be attributed to distinct DNA-binding preferences coupled with differential abilities to engage relatively inaccessible chromatin. We propose that varying preferences for preexisting chromatin states enables the functional diversification of paralogous TFs.
2023-10-04 | GSE244409 | GEO
Project description:The DNA-binding activities of transcription factors (TFs) are influenced by both intrinsic sequence preferences and extrinsic interactions with cell-specific chromatin landscapes and other regulatory proteins. Disentangling the roles of these determinants in TF-DNA binding remains challenging. For instance, the FoxA subfamily of Forkhead domain TFs are known pioneer factors, yet their binding varies across cell types, pointing to a combination of intrinsic and extrinsic forces guiding their binding. How such sequence and chromatin influences vary across related Forkhead domain TFs remains mostly uncharacterized. Here, we present a principled approach to compare the relative contributions of intrinsic DNA sequence preference and cell-specific chromatin environments to a TF’s DNA-binding activities. We over-express a selection of Fox TFs in mouse embryonic stem (mES) cells, which offer a platform to contrast each TF's binding activity within the same preexisting chromatin background. By developing and applying a neural network that jointly models sequence and chromatin data, we can evaluate how sequence and preexisting chromatin features contribute to induced TF binding, both at individual sites and genome-wide. We demonstrate that Fox TFs bind different DNA targets, and drive differential gene expression patterns, even when induced in identical chromatin settings. Differential Fox binding activities can be attributed to distinct DNA-binding preferences coupled with differential abilities to engage relatively inaccessible chromatin. We propose that varying preferences for preexisting chromatin states enables the functional diversification of paralogous TFs.
2023-10-04 | GSE244408 | GEO
Project description:Although Hox genes encode for conserved transcription factors (TFs), they are further divided into anterior, central and posterior groups based on their DNA-binding domain similarity. The posterior Hox group expanded in the deuterostome clade and patterns caudal and distal structures. We aimed to address how similar Hox TFs diverge to induce different positional identities. We studied Hox TF DNA-binding and regulatory activity during an in vitro motor neuron differentiation system that recapitulates embryonic development. We found diversity in the genomic binding profiles of different Hox TFs, even among the posterior group paralogs that share similar DNA-binding domains. These differences in genomic binding were explained by differing abilities to bind to previously inaccessible sites. For example, the posterior group HOXC9 had a greater ability to bind occluded sites than the posterior HOXC10, producing different binding patterns and driving differential gene expression programs. From these results, we propose that the differential abilities of posterior Hox TFs to bind to previously inaccessible chromatin drive patterning diversification.This article has an associated 'The people behind the papers' interview.
| S-EPMC7710020 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-09-06 | GSE142379 | GEO
Project description:Reprogramming cells from one fate to another, using transcription factors, generates cells for research and potential therapy, yet little is known about the initial engagement of reprogramming factors with the genome. We mapped the interactions between Oct4, Sox2, Klf4, and c-Myc (OSKM) and the human genome during the first 48 hours of cellular reprogramming to pluripotency. Unlike that reported in ES/iPS cells, we find extensive overlap in the initial binding of OSKM, demonstrating that the initial regulatory network differs markedly from that in pluripotency. OSK act as pioneer factors for c-Myc, and c-Myc enhances the engagement of OSK, including at many genes that are required for conversion to pluripotency. Distal enhancer sites in closed chromatin dominate the initial OSKM distribution. Hierarchical chromatin binding during reprogramming resembles that employed during development. Four chIP-seq data sets (Oct4, Sox2, Klf4, and c-Myc) are included, one lane per factor, no replicates. Also included is an input lane from the same conditions and two mock lentiviral controls (no exogenous OSKM factors) treated with Oct4 IP and c-Myc IP.
2012-11-16 | E-GEOD-36570 | biostudies-arrayexpress
Project description:While Hox genes encode for similar transcription factors (TFs), they induce different fates across body axes. We sought to understand how Hox TF genomic binding preferences relate to their patterning activities during neuronal differentiation. To generate the required neuronal diversity for locomotor activity, Hox TFs specify spinal motor neuron and interneuron subtypes along the rostro-caudal axis. Our data revelated that Hoxc6 and Hoxc8 of the central group induce limb-innervating fates by binding to the same sites. On the other hand, the posterior group Hox genes assign different positional identities: Hoxc9 (thoracic), Hoxc10 (limb-innervating) and Hox13 (axial elongation termination) by binding to distinct sites with the same primary motif. We find that their genomic binding distributions are explained by differential abilities to bind to previously inaccessible chromatin. Thus, the vertebrate posterior Hox expansion and its associated patterning diversification is the product of their differential abilities to associate with less accessible chromatin.
2020-09-06 | GSE142378 | GEO
Project description:While Hox genes encode for similar transcription factors (TFs), they induce different fates across body axes. We sought to understand how Hox TF genomic binding preferences relate to their patterning activities during neuronal differentiation. To generate the required neuronal diversity for locomotor activity, Hox TFs specify spinal motor neuron and interneuron subtypes along the rostro-caudal axis. Our data revelated that Hoxc6 and Hoxc8 of the central group induce limb-innervating fates by binding to the same sites. On the other hand, the posterior group Hox genes assign different positional identities: Hoxc9 (thoracic), Hoxc10 (limb-innervating) and Hox13 (axial elongation termination) by binding to distinct sites with the same primary motif. We find that their genomic binding distributions are explained by differential abilities to bind to previously inaccessible chromatin. Thus, the vertebrate posterior Hox expansion and its associated patterning diversification is the product of their differential abilities to associate with less accessible chromatin.
2020-09-06 | GSE142377 | GEO
Project description:While Hox genes encode for similar transcription factors (TFs), they induce different fates across body axes. We sought to understand how Hox TF genomic binding preferences relate to their patterning activities during neuronal differentiation. To generate the required neuronal diversity for locomotor activity, Hox TFs specify spinal motor neuron and interneuron subtypes along the rostro-caudal axis. Our data revelated that Hoxc6 and Hoxc8 of the central group induce limb-innervating fates by binding to the same sites. On the other hand, the posterior group Hox genes assign different positional identities: Hoxc9 (thoracic), Hoxc10 (limb-innervating) and Hox13 (axial elongation termination) by binding to distinct sites with the same primary motif. We find that their genomic binding distributions are explained by differential abilities to bind to previously inaccessible chromatin. Thus, the vertebrate posterior Hox expansion and its associated patterning diversification is the product of their differential abilities to associate with less accessible chromatin.
2020-09-06 | GSE142375 | GEO
Project description:Reprogramming cells from one fate to another, using transcription factors, generates cells for research and potential therapy, yet little is known about the initial engagement of reprogramming factors with the genome. We mapped the interactions between Oct4, Sox2, Klf4, and c-Myc (OSKM) and the human genome during the first 48 hours of cellular reprogramming to pluripotency. Unlike that reported in ES/iPS cells, we find extensive overlap in the initial binding of OSKM, demonstrating that the initial regulatory network differs markedly from that in pluripotency. OSK act as pioneer factors for c-Myc, and c-Myc enhances the engagement of OSK, including at many genes that are required for conversion to pluripotency. Distal enhancer sites in closed chromatin dominate the initial OSKM distribution. Hierarchical chromatin binding during reprogramming resembles that employed during development.
2012-11-16 | GSE36570 | GEO