Abstract:The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depends on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However, how chromatin players contribute to the assembly of transcriptional condensates is poorly understood. By interrogating the effect of
KMT2D
(also … Show more
“…Indeed, recent findings corroborate that transcriptional condensates are based on fuzzy and weak cooperative interactions between the IDRs of TFs and cofactors ( Fig. 2A ) ( Boija et al, 2018 ; Cho et al, 2018 ; Chong et al, 2018 ; Sabari et al, 2018 ; Shrinivas et al, 2019 ; Sabari, 2020 ; Ma et al, 2021 ), and suggest that mutations in the IDRs of transcriptional regulators can lead to aberrant phase separation and impaired formation of transcriptional condensates, thus resulting in DDs ( Basu et al, 2020 ; Fasciani et al, 2020 ; Tsang et al, 2020 ). Fig.…”
Section: A Unified Explanatory Frameworksupporting
Many human birth defects and neurodevelopmental disorders are caused by loss-of-function mutations in a single copy of transcription factor (TF) and chromatin regulator genes. Although this dosage sensitivity has long been known, how and why haploinsufficiency (HI) of transcriptional regulators leads to developmental disorders (DDs) is unclear. Here I propose the hypothesis that such DDs result from defects in cell fate determination that are based on disrupted bistability in the underlying gene regulatory network (GRN). Bistability, a crucial systems biology concept to model binary choices such as cell fate decisions, requires both positive feedback and ultrasensitivity, the latter often achieved through TF cooperativity. The hypothesis explains why dosage sensitivity of transcriptional regulators is an inherent property of fate decisions, and why disruption of either positive feedback or cooperativity in the underlying GRN is sufficient to cause disease. I present empirical and theoretical evidence in support of this hypothesis and discuss several issues for which it increases our understanding of disease, such as incomplete penetrance. The proposed framework provides a mechanistic, systems-level explanation of HI of transcriptional regulators, thus unifying existing theories, and offers new insights into outstanding issues of human disease.
This article has an associated Future Leader to Watch interview with the author of the paper.
“…Indeed, recent findings corroborate that transcriptional condensates are based on fuzzy and weak cooperative interactions between the IDRs of TFs and cofactors ( Fig. 2A ) ( Boija et al, 2018 ; Cho et al, 2018 ; Chong et al, 2018 ; Sabari et al, 2018 ; Shrinivas et al, 2019 ; Sabari, 2020 ; Ma et al, 2021 ), and suggest that mutations in the IDRs of transcriptional regulators can lead to aberrant phase separation and impaired formation of transcriptional condensates, thus resulting in DDs ( Basu et al, 2020 ; Fasciani et al, 2020 ; Tsang et al, 2020 ). Fig.…”
Section: A Unified Explanatory Frameworksupporting
Many human birth defects and neurodevelopmental disorders are caused by loss-of-function mutations in a single copy of transcription factor (TF) and chromatin regulator genes. Although this dosage sensitivity has long been known, how and why haploinsufficiency (HI) of transcriptional regulators leads to developmental disorders (DDs) is unclear. Here I propose the hypothesis that such DDs result from defects in cell fate determination that are based on disrupted bistability in the underlying gene regulatory network (GRN). Bistability, a crucial systems biology concept to model binary choices such as cell fate decisions, requires both positive feedback and ultrasensitivity, the latter often achieved through TF cooperativity. The hypothesis explains why dosage sensitivity of transcriptional regulators is an inherent property of fate decisions, and why disruption of either positive feedback or cooperativity in the underlying GRN is sufficient to cause disease. I present empirical and theoretical evidence in support of this hypothesis and discuss several issues for which it increases our understanding of disease, such as incomplete penetrance. The proposed framework provides a mechanistic, systems-level explanation of HI of transcriptional regulators, thus unifying existing theories, and offers new insights into outstanding issues of human disease.
This article has an associated Future Leader to Watch interview with the author of the paper.
“…The behaviors of proteins involved in chromatin and transcriptional condensates provide instructive examples of selective biomolecular partitioning. Some euchromatic and heterochromatic proteins selectively partition into condensates formed by other components of euchromatin and heterochromatin, and this partitioning behavior may contribute to the separation of these two compartments in the nucleus (Fasciani et al, 2020;Li et al, 2020). Phosphorylation of RNA polymerase II during transcription initiation causes the polymerase to switch between transcriptional and splicing condensates, illustrating how IDR modification can change the partitioning behavior of a macromolecule (Guo et al, 2019;Kwon et al, 2013).…”
“…Third, one-third of KMT2D targets contained a TEAD binding site, pointing to an interplay between KMT2D/COMPASS complex and TEAD. This hypothesis is supported by the recent evidence of interaction between KMT2D and YAP/TAZ 54 , a known interactor of the TEAD family 55 . In particular, we found TEAD2 dysregulated both in fibroblasts and neurons, where it emerged as KMT2D direct target responsible for a vast portion of transcriptional dysregulation.…”
Kabuki syndrome (KS) is a rare multisystem disorder, characterized by intellectual disability, growth delay, and distinctive craniofacial features. It is mostly caused by de novo mutations of KMT2D, which is responsible for histone H3lysine 4 mono-methylation (H3K4me1) that marks active and poised enhancers. We assessed the impact of KMT2D mutations on chromatin and transcriptional regulation in a cohort of multiple KS1 tissues, including primary patient samples and disease-relevant lineages, namely cortical neurons (iN), neural crest stem cells (NCSC), and mesenchymal cells (MC). In parallel, we generated an isogenic line derived from human embryonic stem cells (hESC) for the stepwise characterization of neural precursors and mature neurons. We found that transcriptional dysregulation was particularly pronounced in cortical neurons and widely affected synapse activity pathways. This was consistent with highly specific alterations of spontaneous network-bursts patterns evidenced by Micro-electrode-array (MEA)-based neural network. Profiling of H3K4me1 unveiled the almost complete uncoupling between this chromatin mark and the effects on transcription, which is instead reflected by defects in H3K27ac. Finally, we identified the direct targets of KMT2D in mature cortical neurons, uncovering TEAD2 as the main mediator of KMT2D haploinsufficiency. Our results uncover the multi-tissue architecture of KS1 dysregulation and define a unique electrical phenotype and its molecular underpinnings for the cortical neuronal lineage.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
