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Dr. Kaela Varberg Awarded NIH Grant to Investigate the Role of ASCL2 in Trophoblast Cell Lineage Development

STORIES

Dr. Kaela Varberg Awarded NIH Grant to Investigate the Role of ASCL2 in Trophoblast Cell Lineage Development

Headshot of Kaela M Varberg, PhD
Kaela M Varberg, PhD
Doctoral Research Faculty; Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Research Assistant Professor of Pathology, University of Kansas School of Medicine
Full Biography

Kaela Varberg, PhD, Medical Administration, was awarded a three-year, $747,000 R00 Pathway to Independence Award from Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health.

Dr. Varberg’s study titled, “Regulation of Invasive Trophoblast Cell Lineage Development,” will identify gene targets of Achaete-Scute Family Basic Helix-Loop-Helix Transcription Factor 2 (ASCL2) and place ASCL2 within the regulatory hierarchy controlling invasive trophoblast cell lineage development. This work will leverage innovative rat models and human trophoblast stem cells.

Uterine vascular remodeling occurs during pregnancy to meet increasing fetal nutrient demands. This remodeling includes modification of the uterine spiral arteries into low resistance vessels for supplying blood to the developing fetus. Central to uterine spiral artery remodeling are invasive trophoblast cells which, in humans, are called extravillous trophoblast (EVT). Impaired EVT cell development, and thus, insufficient uterine spiral artery remodeling, leads to low quality fetal conditions and adverse pregnancy outcomes, which include pregnancy loss, preeclampsia, intrauterine growth restriction, and preterm birth.

“We identified that ASCL2 is a critical and conserved regulator of EVT cell lineage development. Depletion of ASCL2 in human trophoblast stem (TS) cells inhibits EVT cell formation,” explains Dr. Varberg. “Similarly, global depletion of ASCL2 in vivo disrupts placental development and causes embryonic lethality in the rat.”

ASCL2 is a Protein Coding gene that is critical for hemochorial placenta development. However, the molecular mechanisms by which ASCL2 directs EVT cell lineage development are unknown.

“Our established human trophoblast stem cell lines and protocols for generating mutant rat models will allow us to directly test our central hypothesis that ASCL2 controls EVT cell lineage development during the formation of a placenta,” said Dr. Varberg.

To investigate higher order actions of ASCL2 on the epigenomic landscape of the EVT cell lineage, Dr. Varberg’s team will identify how ASCL2 depletion alters DNA methylation, chromatin accessibility and conformation using whole genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatinsequencing (ATAC-seq), and chromatin capture using Hi-C.

To identify direct genomic targets of ASCL2 the team will perform chromatin immunoprecipitation sequencing (ChIP-seq) in EVT cells. ASCL2 regulation of trophoblast cell development and invasion will then be evaluated in vivo using a newly established model of invasive trophoblast cell specific depletion based on breeding Prl7b1 Cre recombinase and Ascl2 floxed rats.

“To examine ASCL2-regulated trophoblast cell development in rat placentas we will conduct single cell RNA-sequencing (scRNA-seq) and single cell ATAC-seq,” said Dr. Varberg.

Dr. Varberg’s long-term career goal is to identify how dysregulated spiral artery remodeling leads to a spectrum of diseases ranging from fetal growth restriction to preeclampsia.

The contents are those of the investigator and do not necessarily represent the official views of, nor an endorsement, by NIH, or the U.S. Government.