Biology subjects

Gordillo, M.

Publications and source records attributed to Gordillo, M..

3 recordsLinked to original sources

bioRxiv2025

GATA6 Mediates Endoderm and Mesoderm Progenitor Fate Driven by WNT and NODAL Signaling

During gastrulation, NODAL and WNT signaling drives distinct gene regulatory networks (GRNs) to promote pluripotency exit, specify progenitor fate, and direct lineage differentiation. Here, we employ murine embryonic stem cell directed differentiation toward endoderm and mesoderm lineages to reveal a crucial role of GATA6 during anterior primitive streak-derived progenitor segregation. GATA6 is known to direct by default extra-embryonic endoderm. To promote definitive endoderm fate, GATA6 reinforces the endoderm GRN driven by NODAL while repressing the mesoderm GRN through down-regulation of WNT activity. During progression of mesoderm differentiation, GATA6 induces a switch in the transcriptional output regulated by WNT, promoting lateral mesoderm specification and repression of paraxial mesoderm fate. Thus, this single transcription factor mediates formation of four distinct tissue types, depending on integration of NODAL/WNT activities. Regulation of Eomes and T/Bra expression during anterior primitive streak progression is an essential function of GATA6 during the specification of endoderm or mesoderm fate.

developmental biology↗

bioRxiv2024

GATA6 regulates WNT and BMP programs to pattern precardiac mesoderm during the earliest stages of human cardiogenesis

Haploinsufficiency for GATA6 is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hours of cardiac differentiation is sufficient to partially rescue CPC and CM defects in GATA6 heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by human GATA6 mutations.

developmental biology↗

bioRxiv2022

Lipids Maintain Genomic Stability and Developmental Potency of Murine Pluripotent Stem Cells

Lipids play vital roles in cellular homeostasis and regulate pluripotency of human stem cells. However, the impact of lipids on murine pluripotent stem cells is unclear. While Mek1/2 and Gsk3{beta} inhibition ("2i") supports the maintenance of murine embryonic stem cells (ESCs) in a homogenous naive state, prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential. Additionally, 2i fails to support derivation and culture of fully potent female ESCs. Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin (AlbuMAX) undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture. Mechanistically, lipids in AlbuMAX impact intracellular metabolism including nucleotide biosynthesis, lipid biogenesis, and TCA cycle intermediates, with enhanced expression of ZCAN4 and DNMT3s that prevent telomere shortening and DNA hypomethylation. In concert with 2i, lipids induce a formative-like pluripotent state through direct stimulation of Mek-mediated Erk2 phosphorylation, which also alleviates X chromosome loss in female ESCs. Importantly, both male and female "all-ESC" mice can be generated from de novo derived ESCs using AlbuMAX-based media. Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.

developmental biology↗