MEIS transcription factors in development and disease

Schulte, Dorothea; Geerts, Dirk

doi:10.1242/dev.174706

Cited by 53 publications

(56 citation statements)

References 172 publications

(159 reference statements)

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“…2 ), its redundant paralogs meis2a and meis2b were also enriched in hand2 -expressing zebrafish progenitors ( Fig. S4 ) (Schulte and Geerts, 2019). This HAND2 -expressing group of mesothelioma tumors did not cluster notably with tumors featuring differential expression of the common mesothelioma-associated tumor suppressor genes BAP1 and NF2 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Crowell

Nieuwenhuize

et al. 2020

Preprint

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The mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post-gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma.

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Section: Resultsmentioning

confidence: 99%

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Crowell

Nieuwenhuize

et al. 2020

Preprint

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“…Meis1 and Meis2 encode transcription factors belonging to the three amino acid loop extension (TALE) family of homeodomain-containing proteins [48,49]. Previous studies suggested that Nr2f genes are activated by RA in Ciona, zebrafish, and mouse cell lines [50][51][52][53].…”

Section: Plos Biologymentioning

confidence: 99%

Discovery of genes required for body axis and limb formation by global identification of retinoic acid–regulated epigenetic marks

et al. 2020

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Identification of target genes that mediate required functions downstream of transcription factors is hampered by the large number of genes whose expression changes when the factor is removed from a specific tissue and the numerous binding sites for the factor in the genome. Retinoic acid (RA) regulates transcription via RA receptors bound to RA response elements (RAREs) of which there are thousands in vertebrate genomes. Here, we combined chromatin immunoprecipitation sequencing (ChIP-seq) for epigenetic marks and RNA-seq on trunk tissue from wild-type and Aldh1a2-/-embryos lacking RA synthesis that exhibit body axis and forelimb defects. We identified a relatively small number of genes with altered expression when RA is missing that also have nearby RA-regulated deposition of histone H3 K27 acetylation (H3K27ac) (gene activation mark) or histone H3 K27 trimethylation (H3K27me3) (gene repression mark) associated with conserved RAREs, suggesting these genes function downstream of RA. RA-regulated epigenetic marks were identified near RA target genes already known to be required for body axis and limb formation, thus validating our approach; plus, many other candidate RA target genes were found. Nuclear receptor 2f1 (Nr2f1) and nuclear receptor 2f2 (Nr2f2) in addition to Meis homeobox 1 (Meis1) and Meis homeobox 2 (Meis2) gene family members were identified by our approach, and double knockouts of each family demonstrated previously unknown requirements for body axis and/or limb formation. A similar epigenetic approach can be used to determine the target genes for any transcriptional regulator for which a knockout is available.

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“…In animals, they have been grouped into five classes, PBC, MEINOX, TGIF, IRO and MKX, based on the sequence of the HD itself and conserved, class-specific motifs flanking the HD ( Figure 1B). The developmental functions of individual TALE-HD genes and the defects associated with their mutation in animal models or in human diseases have been covered by a series of excellent recent reviews and will therefore not be discussed in detail (Kim et al, 2012;Blasi et al, 2017;Schulte and Geerts, 2019;Selleri et al, 2019). Instead, we here provide an overview of the different PTMs detected in mouse and human TALE-HD TFs and explore how such PTMs may help to convey functional specificity among these structurally similar proteins.…”

Section: Tale-hd Proteinsmentioning

confidence: 99%

Posttranslational Modifications in Conserved Transcription Factors: A Survey of the TALE-Homeodomain Superclass in Human and Mouse

Reichlmeir

Elias

Schulte

2021

Front. Cell Dev. Biol.

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Transcription factors (TFs) guide effector proteins like chromatin-modifying or -remodeling enzymes to distinct sites in the genome and thereby fulfill important early steps in translating the genome’s sequence information into the production of proteins or functional RNAs. TFs of the same family are often highly conserved in evolution, raising the question of how proteins with seemingly similar structure and DNA-binding properties can exert physiologically distinct functions or respond to context-specific extracellular cues. A good example is the TALE superclass of homeodomain-containing proteins. All TALE-homeodomain proteins share a characteristic, 63-amino acid long homeodomain and bind to similar sequence motifs. Yet, they frequently fulfill non-redundant functions even in domains of co-expression and are subject to regulation by different signaling pathways. Here we provide an overview of posttranslational modifications that are associated with murine and human TALE-homeodomain proteins and discuss their possible importance for the biology of these TFs.

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MEIS transcription factors in development and disease

Cited by 53 publications

References 172 publications

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Discovery of genes required for body axis and limb formation by global identification of retinoic acid–regulated epigenetic marks

Posttranslational Modifications in Conserved Transcription Factors: A Survey of the TALE-Homeodomain Superclass in Human and Mouse

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