RNA‐Seq and ChIP‐Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes
ABSTRACT Transcription factor TBX4 rare variants associate with pulmonary arterial hypertension (PAH), particularly in children, and are the second most common cause of heritable PAH. However, TBX4's down‐stream targets and the molecular and cellular pathways these targets regulate remain large...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Pulmonary Circulation |
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| Online Access: | https://doi.org/10.1002/pul2.70058 |
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| author | Ying Cai Ling Yan Joy D. Cogan Lora K. Hedges Bethany Nunley Nick Negretti Jennifer M. S. Sucre James West Eric D. Austin Rizwan Hamid |
| author_facet | Ying Cai Ling Yan Joy D. Cogan Lora K. Hedges Bethany Nunley Nick Negretti Jennifer M. S. Sucre James West Eric D. Austin Rizwan Hamid |
| author_sort | Ying Cai |
| collection | DOAJ |
| description | ABSTRACT Transcription factor TBX4 rare variants associate with pulmonary arterial hypertension (PAH), particularly in children, and are the second most common cause of heritable PAH. However, TBX4's down‐stream targets and the molecular and cellular pathways these targets regulate remain largely unknown in PAH. We combined RNA‐seq and ChIP‐seq results to identify TBX4 direct targets in lung fibroblasts and pericytes, respectively. There were 555 genes with altered expression with TBX4 knockdown in both fibroblasts and pericytes by RNA‐seq, and which also were found to be bound by TBX4 by ChIP‐seq. Gene ontology analysis found that these were dominated by genes related to extracellular matrix, actin organization, and migration guidance, although there were also significant groups related to serine/threonine kinase signaling, GTPase mediated signaling, and glycoprotein metabolism. Migration and proliferation studies using TBX4 knockdown fibroblasts confirmed functional effects. These studies provide the first insights into how genes and pathways regulated by TBX4 are impacted and inform future studies about the key biological processes that lead to PAH in patients who carry pathologic TBX4 rare variants. |
| format | Article |
| id | doaj-art-c7404fba4ea842cca681ea4581dcf07e |
| institution | OA Journals |
| issn | 2045-8940 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pulmonary Circulation |
| spelling | doaj-art-c7404fba4ea842cca681ea4581dcf07e2025-08-20T01:50:07ZengWileyPulmonary Circulation2045-89402025-01-01151n/an/a10.1002/pul2.70058RNA‐Seq and ChIP‐Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and PericytesYing Cai0Ling Yan1Joy D. Cogan2Lora K. Hedges3Bethany Nunley4Nick Negretti5Jennifer M. S. Sucre6James West7Eric D. Austin8Rizwan Hamid9Division of Medical Genetics and Genomic Medicine Vanderbilt University Medical Center Nashville Tennessee USADivision of Medical Genetics and Genomic Medicine Vanderbilt University Medical Center Nashville Tennessee USADivision of Medical Genetics and Genomic Medicine Vanderbilt University Medical Center Nashville Tennessee USADivision of Allergy, Immunology, and Pulmonary Medicine Vanderbilt University Medical Center Nashville Tennessee USADivision of Medical Genetics and Genomic Medicine Vanderbilt University Medical Center Nashville Tennessee USAMildred Stahlman Division of Neonatology Vanderbilt University Medical Center Nashville Tennessee USAMildred Stahlman Division of Neonatology Vanderbilt University Medical Center Nashville Tennessee USADivision of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine Vanderbilt University Medical Center Nashville Tennessee USADivision of Allergy, Immunology, and Pulmonary Medicine Vanderbilt University Medical Center Nashville Tennessee USADivision of Medical Genetics and Genomic Medicine Vanderbilt University Medical Center Nashville Tennessee USAABSTRACT Transcription factor TBX4 rare variants associate with pulmonary arterial hypertension (PAH), particularly in children, and are the second most common cause of heritable PAH. However, TBX4's down‐stream targets and the molecular and cellular pathways these targets regulate remain largely unknown in PAH. We combined RNA‐seq and ChIP‐seq results to identify TBX4 direct targets in lung fibroblasts and pericytes, respectively. There were 555 genes with altered expression with TBX4 knockdown in both fibroblasts and pericytes by RNA‐seq, and which also were found to be bound by TBX4 by ChIP‐seq. Gene ontology analysis found that these were dominated by genes related to extracellular matrix, actin organization, and migration guidance, although there were also significant groups related to serine/threonine kinase signaling, GTPase mediated signaling, and glycoprotein metabolism. Migration and proliferation studies using TBX4 knockdown fibroblasts confirmed functional effects. These studies provide the first insights into how genes and pathways regulated by TBX4 are impacted and inform future studies about the key biological processes that lead to PAH in patients who carry pathologic TBX4 rare variants.https://doi.org/10.1002/pul2.70058ChIP‐seqextracellular matrix (ECM)pulmonary arterial hypertension (PAH)RNA‐seqT‐Box 4 (TBX4) |
| spellingShingle | Ying Cai Ling Yan Joy D. Cogan Lora K. Hedges Bethany Nunley Nick Negretti Jennifer M. S. Sucre James West Eric D. Austin Rizwan Hamid RNA‐Seq and ChIP‐Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes Pulmonary Circulation ChIP‐seq extracellular matrix (ECM) pulmonary arterial hypertension (PAH) RNA‐seq T‐Box 4 (TBX4) |
| title | RNA‐Seq and ChIP‐Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes |
| title_full | RNA‐Seq and ChIP‐Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes |
| title_fullStr | RNA‐Seq and ChIP‐Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes |
| title_full_unstemmed | RNA‐Seq and ChIP‐Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes |
| title_short | RNA‐Seq and ChIP‐Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes |
| title_sort | rna seq and chip seq identification of unique and overlapping target genes and pathways regulated by tbx4 in human pulmonary fibroblasts and pericytes |
| topic | ChIP‐seq extracellular matrix (ECM) pulmonary arterial hypertension (PAH) RNA‐seq T‐Box 4 (TBX4) |
| url | https://doi.org/10.1002/pul2.70058 |
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