Cohesin and CTCF differentially regulate spatiotemporal runx1 expression during zebrafish development

Marsman, Judith; O'Neill, Adam C; Kao, Betty; Rhodes, Jenny M.; Meier, Michael; Antony, Jisha; Mönnich, Maren; Horsfield, Julia A.

doi:10.1016/j.bbagrm.2013.11.007

Cited by 41 publications

(62 citation statements)

References 57 publications

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“…During zebrafish development, runx1 is expressed in the posterior lateral plate mesoderm (PLM). We observed defects in runx1 expression patterns recapitulating prior studies, 23,24 with runx1 expression either partially or completely absent in rad21a morphants (Figures 2A–C). Runx1 expression was rescued by co-injection of MO with human WT RAD21 mRNA .…”

Section: Resultssupporting

confidence: 87%

“…Since one of the main target genes activated by RAD21 is RUNX1 23,24 we investigated whether mutated RAD21 could hamper its transcription activity: indeed, the affected individual’s LCLs showed significantly reduced RUNX1 expression compared to controls (Figure 1C). Similarly, transfection of mutant RAD21 cDNA in HEK293 cells and subsequent RT-qPCR revealed a significant decrease in RUNX1 expression (p=0.0028, Student’s t-test) compared to cells transfected with wild-type RAD21 cDNA (Supplementary Figure 3E).…”

Section: Resultsmentioning

confidence: 99%

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Mutations in RAD21 Disrupt Regulation of APOB in Patients With Chronic Intestinal Pseudo-Obstruction

et al. 2015

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Background & Aims Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimicks a mechanical sub-occlusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and indentify potential biomarkers. Methods We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of mRNA and proteins were analyzed by quantitative reverse transcription PCR, immunoblot, and mobility shift assays. cDNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a MO). Gut tissues were collected and analyzed. Results We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a MO zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 is also overexpressed in sporadic CIPO in sera and gut biopsies. Conclusions Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and development of enteric neurons.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Mutations in RAD21 Disrupt Regulation of APOB in Patients With Chronic Intestinal Pseudo-Obstruction

et al. 2015

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“…For example, cohesin abrogation leads to increased expression of the transcription factor Runx1 [48,49] an important regulator of HSCs and megakaryocytes. Whether this upregulation in Runx1 reflects changes across all HSPC lineages, or reflects altered differentiation is an important unanswered question.…”

Section: Cohesin Mutations In Ds-amklmentioning

confidence: 99%

Cohesin Mutations in Myeloid Malignancies

et al. 2017

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Acute Myeloid Leukemia (AML) is a hematologic malignancy with a poor prognosis. Recent genome-wide sequencing studies have identified frequent mutations in genes encoding members of the cohesin complex. Mutations in cohesin contribute to myeloid malignancies by conferring enhanced self-renewal of hematopoietic stem and progenitor cells but the mechanisms behind this phenotype have not been fully elucidated. Of note, cohesin mutations are highly prevalent in acute megakaryocytic leukemia associated with Down syndrome (DS-AMKL), where they occur in over half of patients. Evidence suggests that cohesin mutations alter gene expression through changes in chromatin accessibility and/or aberrant targeting of epigenetic complexes. In this review we discuss the pathogenic mechanisms by which cohesin mutations contribute to myeloid malignancies.

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“…Mutation of the cohesin loading factor NIPBL is responsible for around 65% cases of Cornelia de Lange Syndrome (CdLS [MIM 122470]), while mutations in subunits account for 5-10% cases [11], indicating that intact cohesin function is important for normal human development. The gene regulatory function of cohesin is independent of its role in cell cycle [12][13][14][15] and can be remarkably tissue-specific [16][17][18][19], indicating that it has an important but as yet poorly understood role in cell type-specific transcription. Although the exact mechanism by which cohesin regulates gene expression is unclear, it has been shown to facilitate long-range interactions between DNA elements, including interactions between fetal bovine serum (FBS) in a 37°C humidified incubator at 5% CO 2 .…”

Section: Introductionmentioning

confidence: 98%