TWIST1 homodimers and heterodimers orchestrate lineage-specific differentiation

Fan, Xiaochen; Waardenberg, Ashley J.; Demuth, Madeleine; Osteil, Pierre; Sun, Jing; Loebel, David A.F.; Graham, Mark E.; Tam, Patrick; Fossat, Nicolas

doi:10.1101/672824

Cited by 7 publications

(11 citation statements)

References 66 publications

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“…Differential binding analysis of TWIST1 using sumnormalized peptide-spectrum match (PSM) values (Figure S2B,C;see Methods) revealed 140 putative TWIST1 interactors in NCCs (P < 0.05; Fold-change > 3; PSM# > 2; Figure 1B, Table S1). These candidates included 4 of 56 known TWIST1 interactors, including TCF3, TCF4, TCF12 and GLI3 (overlap odds ratio = 18.05, Chi-squared test p-value = 0.0005; Agile Protein Interactomes DataServer [APID]) (Alonso-Lopez et al, 2019;Fan et al, 2020). A. BioID procedure to identify TWIST1-interacting partners in neural crest stem cells (NCCs).…”

Section: Deciphering the Twist1 Protein Interactome In Cranial Nccs Umentioning

confidence: 99%

TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation

Fan

Masamsetti

Sun

et al. 2020

Preprint

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Protein interaction is critical molecular regulatory activity underlining cellular functions and precise cell fate choices. Using TWIST1 BioID-proximity-labelling and network propagation analyses, we discovered and characterized a TWIST-chromatin regulatory module (TWIST1-CRM) in the neural crest cell (NCC). Combinatorial perturbation of core members of TWIST1-CRM: TWIST1, CHD7, CHD8, and WHSC1 in cell models and mouse embryos revealed that loss of the function of the regulatory module resulted in abnormal specification of NCCs and compromised craniofacial tissue patterning. Our results showed that in the course of cranial neural crest differentiation, phasic activity of TWIST1 and the interacting chromatin regulators promote the choice of NCC fate while suppressing neural stem cell fates, and subsequently enhance ectomesenchyme potential and cell motility. We have revealed the connections between TWIST1 and potential neurocristopathy factors which are functionally interdependent in NCC specification. Moreover, the NCC module participate in the genetic circuit delineating dorsal-ventral patterning of neural progenitors in the neuroepithelium.

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Section: Deciphering the Twist1 Protein Interactome In Cranial Nccs Umentioning

confidence: 99%

TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation

Fan

Masamsetti

Sun

et al. 2020

Preprint

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“…We observe expression of both ubiquitous and lineage-specific bHLH binding partners (e.g. HAND2 and PRRX1, respectively) (Fan et al, 2020) Proceeding this was activation of a module including IRX3 and TWIST1, revealing these as the first transcription factors activated along the limb lineage. While IRX3 is known to be active in the early somatic LPM (Funayama et al, 1999), its role in limb development is not well understood, and deletion of Irx3 does not produce an overt phenotype in mouse.…”

Section: Discussionmentioning

confidence: 75%

“…HAND1 and TWIST1 possess known roles in gut and limb development (Firulli et al, 1998;Wu and Howard, 2002;Krawchuk et al, 2010;Loebel et al, 2012), but are yet to be examined during LPM subdivision. Interestingly, bHLH transcription factors form combinations of homo-and heterodimers with unique binding partners to dynamically regulate different biological processes (Fan et al, 2020). We observe expression of both ubiquitous and lineage-specific bHLH binding partners (e.g.…”

Section: Discussionmentioning

confidence: 90%

“…The copyright holder for this preprint this version posted January 14, 2022. ; https://doi.org/10.1101/2022.01.13.475748 doi: bioRxiv preprint chicken embryos was detected before and after EMT and proliferation of the limb bud mesenchyme (Figure 4). TWIST1 elicits different biological functions and activity thresholds through dimerization with other transcription factors (Krawchuk et al, 2010;Loebel et al, 2014;Fan et al, 2020), which notably includes the early LPM marker PRRX1 (Fan et al, 2021). Indeed, this role is supported by observations that prrx1a and twist1b cooperatively drive EMT and migration of the LPM in zebrafish, which can be rescued by twist1b knockdown (Ocaña et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Cell lineage specification during development of the anterior lateral plate mesoderm and forelimb field

Newton

Williams

Major

et al. 2022

Preprint

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The lateral plate mesoderm (LPM) is a transient embryonic tissue that gives rise to a diverse range of mature cell types, including the cardiovascular system, the urogenital system, endoskeleton of the limbs, and mesenchyme of the gut. While the genetic processes that drive development of these tissues are well defined, the early cell fate choices underlying LPM development and specification are poorly understood. In this study, we utilize single-cell transcriptomics to define cell lineage specification during development of the anterior LPM and the forelimb field in the chicken embryo. We identify the molecular pathways directing differentiation of the aLPM towards a somatic or splanchnic cell fate, and subsequent emergence of the forelimb mesenchyme. We establish the first transcriptional atlas of progenitor, transitional and mature cell types throughout the early forelimb field and uncover the global signalling pathways which are active during LPM differentiation and forelimb initiation. Specification of the somatic and splanchnic LPM from undifferentiated mesoderm utilizes distinct signalling pathways and involves shared repression of early mesodermal markers, followed by activation of lineage-specific gene modules. We identify rapid activation of the transcription factor TWIST1 in the somatic LPM preceding activation of known limb initiation genes, such as TBX5, which plays a likely role in epithelial-to-mesenchyme transition of the limb bud mesenchyme. Furthermore, development of the somatic LPM and limb is dependent on ectodermal BMP signalling, where BMP antagonism reduces expression of key somatic LPM and limb genes to inhibit formation of the limb bud mesenchyme. Together, these findings provide new insights into molecular mechanisms that drive fate cell choices during specification of the aLPM and forelimb initiation.

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“…Interestingly, overexpression of Hand2, a partner of Twist1 in mandible differentiation and an inhibitor of Runx2, leads to delayed ossification, characterised by ALP low levels,90 which is comparable with our findings. We speculate that the reduced iNCC migration and the delayed ossification in nMSC differentiation could relate to altered expression of TWIST1 in early stages of NCC that would depend on the availability of the bHLH class partners or inhibitor of DNA-binding (ID) proteins 91. Further studies are necessary to test these hypotheses.…”

Section: Discussionmentioning

confidence: 98%

New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involvingTWIST1regulatory elements

et al. 2021

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BackgroundAuriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (PLCB4, GNAI3 and EDN1) and some cases remain unsolved. Here we studied a large unsolved four-generation family.MethodsWe performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells.ResultsThis study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9, which is located over 200 kb telomeric to the top candidate gene TWIST1. Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1, in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells.ConclusionOur findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype.

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TWIST1 homodimers and heterodimers orchestrate lineage-specific differentiation

Cited by 7 publications

References 66 publications

TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation

TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation

Cell lineage specification during development of the anterior lateral plate mesoderm and forelimb field

New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involvingTWIST1regulatory elements

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