Protein-intrinsic properties and context-dependent effects regulate pioneer factor binding and function

Nature Structural & Molecular Biology, Год журнала: 2024, Номер 31(3), С. 548 - 558

Опубликована: Фев. 16, 2024

Язык: Английский

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Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development

Nature Neuroscience, Год журнала: 2024, Номер 27(5), С. 862 - 872

Опубликована: Март 25, 2024

Abstract The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of embryonic basal ganglia. How genetic information determines cell types is unclear. Here we use a combination vivo CRISPR perturbation, lineage tracing ChIP–sequencing analyses show that transcription factor MEIS2 favors development neurons by binding enhancer regions projection-neuron-specific genes during mouse development. requires presence homeodomain DLX5 to direct its functional activity toward appropriate sites. In precursors, LHX6 represses MEIS2–DLX5-dependent activation enhancers. Mutations Meis2 result decreased regulatory enhancers, affecting differentiation. We propose differential model where factors at cis -regulatory elements gene expression programs regulating fate specification ganglionic eminence.

Язык: Английский

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Epithelial-mesenchymal plasticity (EMP) in wound healing: Exploring EMT mechanisms, regulatory network, and therapeutic opportunities

Heliyon, Год журнала: 2024, Номер 10(14), С. e34269 - e34269

Опубликована: Июль 1, 2024

Epithelial-to-mesenchymal transition (EMT), a process by which epithelial cells acquire mesenchymal cell characteristics, is well recognized for its critical role in development, wound healing, tissue fibrosis, and cancer progression. During keratinocytes undergo partially reversible EMT to promote migration re-epithelialization. In this paper, we review the regulatory roles of key signaling pathways (TGF-β, Wnt/β-catenin, Notch) core transcription factors (Snail, Slug, Twist) EMT, explore parallels between re-epithelialization outline recent therapeutic advances future developments targeting healing. addition, call adoption term "epithelial-mesenchymal plasticity" (EMP) more accurately describe dynamic processes that occur during keratinocyte

Язык: Английский

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Systematic dissection of sequence features affecting binding specificity of a pioneer factor reveals binding synergy between FOXA1 and AP-1

Molecular Cell, Год журнала: 2024, Номер 84(15), С. 2838 - 2855.e10

Опубликована: Авг. 1, 2024

Язык: Английский

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Transfer learning reveals sequence determinants of the quantitative response to transcription factor dosage

Cell Genomics, Год журнала: 2025, Номер unknown, С. 100780 - 100780

Опубликована: Фев. 1, 2025

Язык: Английский

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CHD3 Regulates BMP Signalling Response During Cranial Neural Crest Cell Specification

Опубликована: Фев. 19, 2025

CHD3 is a component of the NuRD chromatin remodeling complex. Pathogenic _CHD3_ variants cause Snijders Blok-Campeau Syndrome, neurodevelopmental disorder with variable features including developmental delays, intellectual disability, speech/language difficulties, and craniofacial anomalies. To unveil role in development, we differentiated _CHD3_-KO induced pluripotent stem cells into cranial neural crest (CNCCs). expression low wild-type iPSCs neuroectoderm, but upregulated during CNCC specification, where it opens at BMP-responsive enhancers, to allow binding DLX5 other factors. loss leads repression BMP target genes an imbalance between Wnt signalling, ultimately resulting aberrant mesodermal fate. Consequently, specification fails, replaced by early-mesoderm identity, which can be partially rescued titrating levels. Our findings highlight novel for as pivotal regulator essential proper development.

Язык: Английский

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Distinct gene regulatory dynamics drive skeletogenic cell fate convergence during vertebrate embryogenesis

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 4, 2025

Cell type repertoires have expanded extensively in metazoan animals, with some clade-specific cells being crucial to evolutionary success. A prime example are the skeletogenic of vertebrates. Depending on anatomical location, these originate from three different precursor lineages, yet they converge developmentally towards similar cellular phenotypes. Furthermore, their 'skeletogenic competency' arose at distinct timepoints, thus questioning what extent skeletal body parts rely truly homologous cell types. Here, we investigate how lineage-specific molecular properties integrated gene regulatory level, allow for fate convergence. Using single-cell functional genomics, find that transcription factor profiles inherited states and incorporated enhancer elements. This logic suggests regionalized types, rendering them amenable individualized selection, define adaptive morphologies biomaterial vertebrate skeleton.

Язык: Английский

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The molecular properties of the bHLH TCF4 protein as an intrinsically disordered hub transcription factor

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Март 27, 2025

Transcription factor 4 (TCF4) is a member of the basic helix-loop-helix (bHLH) family transcription factors that guides proper embryogenesis, particularly neurogenesis, myogenesis, heart development and hematopoiesis. The interaction TCF4 with DNA dependent on presence conserved bHLH domain, (b) motif. Most mutations in Tcf4 gene are either associated serious nervous system disorders, such as Pitt-Hopkins syndrome or schizophrenia, lethal. Although essential for function human body, there lack fundamental knowledge about structure since structural studies were previously limited exclusively to its bHLH. Recombinant full-length was expressed bacterial cells purified using chromatographic techniques. To compare properties apo holo form, we determined dissociation constant (KD) TCF4:DNA complex independent methods, including fluorescence polarization (FP), electrophoretic mobility shift assay (EMSA), correlation spectroscopy (FCS). Then compared form relation changes conformation polypeptide chain (hydrogen/deuterium exchange mass spectrometry; HDX-MS), hydrodynamic (e.g., sedimentation-velocity analytical ultracentrifugation; SV-AUC), stability (thermal shift, circular dichroism; CD). We demonstrate molecular characteristics TCF4, dimer which one largest intrinsically disordered proteins (IDPs) described date. According our findings, extensively disordered. Only domain exhibits stable fold. Strikingly, Ephrussi-box (E-box) binding via has no significant effect nature but it does influence dynamic protein. suggest plays role an anchor localizing specific sequences. dual fact regions (IDRs) represent most protein sequence, may act hub regulating expression genes through IDRs gene-specific partners.

Язык: Английский

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Thalidomide-induced limb malformations: an update and reevaluation

Archives of Toxicology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

Язык: Английский

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DNA-guided transcription factor interactions extend human gene regulatory code

Nature, Год журнала: 2025, Номер unknown

Опубликована: Апрель 9, 2025

Язык: Английский

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