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Transcriptomic analysis of lungs with mesnchyme-specific deletion of Sin3a transcriptional regulator

ABSTRACT: Congenital diaphragmatic hernia (CDH) is a common and severe congential malformation characterized by defects in diaphragm, lung, and pulmonary vascular developent. Despite the frequency and severity of CDH, the underlying developmental mechanisms are not understood. We identified SIN3A loss of function sequence variants in two patients with CDH. To understand the genetic and developmental mechanisms of CDH, we generated Sin3a conditional knockout mice that lack Sin3a expression in the lung mesenchyme. SIN3A plays a critcal role during development, directing cell lineage specification and cell cycling. Despite this role, SIN3A sequence variants have not been reported in patients with CDH or other congential malformations. We found that Sin3a CKO mice have abnormal lung stucture at birth into adulthood. To determine the role of Sin3a in lung mesenchymal development, we performed transcriptomic analysis of Sin3a CKO and control lungs at embryonic day 16 (E16) when cell cycling defects were first evident, postnatal day 0 (P0) when lung defects were first evident, and P3 when lung phenotyopes worsened. In this dataset are expression data from dissected embryonic and postnatal lungs of Sin3a CKO and control mice. Sin3a CKO mice have conditional deletion of Sin3a in the lung mesenchyme directed by Tbx4rtta; tetocre (Tbx4rtta; tetocre; Sin3a flox/flox CKO). Control mice are heterozygous for Sin3a in the lung mesenchyme (Tbx4rtta; tetocre; Sin3a flox/WT). These data were used to identify transcriptional changes due to loss of Sin3a in the lung mesenchyme.

ORGANISM(S): Mus musculus

PROVIDER: GSE246305 | GEO | 2023/12/31

REPOSITORIES: GEO

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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.

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Transcriptomic analysis of lungs with mesnchyme-specific deletion of Sin3a transcriptional regulator

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