Unknown,Transcriptomics,Genomics,Proteomics

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ChIP-seq of PBX1, PBX2 and LEF1 in wild-type and Pbx1/Pbx2 double-knockout EpiSCs differentiated in vitro to pre-somitic mesoderm in the first 48 hours of differentiation.

ABSTRACT: In vertebrates, body axis elongation is fuelled by bipotent neuromesodermal progenitors (NMPs), which support the development of both spinal cord and paraxial mesoderm (PM). WNT signalling sustains both NMP expansion and PM differentiation, but the mechanism by which it distinguishes between these alternative fates is unknown. HOX transcription factors have been historically implicated in axial elongation, with their sequential activation playing a fundamental role in timing PM development. PBX1 and PBX2 are obligate anterior HOX cofactors, and therefore they represent prominent candidates for controlling the distinct response to individual HOX factors. In our work, we have demonstrated that PBX proteins generate the DNA-binding context that allows recruitment of the WNT-effector LEF1, and consequently promote the expression of PM genes. Here, we wanted to identify the chromatin binding pattern of PBX1, PBX2 and LEF1 during the first 48 hours of pre-somitic mesoderm (PSM) in vitro differentiation, by performing chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) at different time-points (EpiSCs, 6 hours, 12 hours, 24 hours, 48 hours). To address the impact of PBX loss on LEF1 recruitment to chromatin, we additionally performed ChIP-seq in wild-type (WT) and Pbx1/Pbx2 double-knockout (Pbx1/2-DKO) EpiSCs differentiated in vitro to PSM at different time-points (EpiSCs, 12 hours, 24 hours, 48 hours).

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Luca Mariani

PROVIDER: E-MTAB-9775 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Two critical events that are required for normal transition from fetal to extrauterine life are development of the alveoli that allow for efficient gas exchange in the lung and relaxation of the pulmonary vascular smooth muscle. Patients with congenital diaphragmatic hernia (CDH) have abnormal lung and pulmonary vascular development that results in a lethal combination of lung hypoplasia and pulmonary hypertension. To better understand the mechanisms responsible for abnormal lung and pulmonary vascular development and function we generated Pbx1/2 conditional knockout mice that lack Pbx1 and Pbx2 expression in the lung mesenchyme. Pbx1 has previously been shown to be required for normal diaphragm development, however its role in alveologenesis, and the mechanisms responsible for pulmonary hypertension, has not been studied. We found that Pbx1/2 CKO mice have failure of alveologenesis and die of severe pulmonary hypertension by 2 to 3 weeks of age. In order to better understand the downstream genetic mis-regulation caused by deletion of Pbx1/2, and identify their potential transcriptional targets, we carried out transcriptional profiling of Pbx1/2 CKO and control mice starting at postnatal day 3 (P3), when a histological phenotype first becomes apparent, and then working back to the time of birth (P0), and embryonic day 14 (E14) when the pulmonary vascular smooth muscle is developing. In this dataset are the expression data obtained from dissected embryonic and early postnatal lungs of Pbx1/2 CKO and control mice. Pbx1/2 CKO mice are homozygous null for Pbx2 with conditional deletion of Pbx1 in the lung mesenchyme directed by Tbx4 Cre (Tbx4 Cre/wild-type; Pbx1 flox/flox; Pbx2 delta/delta). Control mice are homozygous null for Pbx2 and are heterozygous for Pbx1 in the lung mesenchyme (Tbx4 Cre/wild-type; Pbx1 flox/wild-type; Pbx2 delta/delta). These data are used to identify the transcriptional targets and down-stream effectors of PBX transciptional regulation in the lung.

Dataset Information

ChIP-seq of PBX1, PBX2 and LEF1 in wild-type and Pbx1/Pbx2 double-knockout EpiSCs differentiated in vitro to pre-somitic mesoderm in the first 48 hours of differentiation.

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