FOXK1 regulates Wnt signalling to promote cardiogenesis

Abstract

Aims Congenital heart disease (CHD) is the most common genetic birth defect, which has considerable morbidity and mortality. We focused on deciphering key regulators that govern cardiac progenitors and cardiogenesis. FOXK1 is a forkhead/winged helix transcription factor known to regulate cell cycle kinetics and is restricted to mesodermal progenitors, somites and the heart. In the present study, we define an essential role for FOXK1 during cardiovascular development. Methods & Results We used the mouse embryoid body system to differentiate control and Foxk1 KO ESCs into mesodermal, cardiac progenitor cells and mature cardiac cells. Using flow cytometry, immunohistochemistry, cardiac beating, transcriptional and ChIP qPCR assays, bulk RNAseq and ATACseq analyses, FOXK1 was observed to be an important regulator of cardiogenesis. Flow cytometry analyses revealed perturbed cardiogenesis in Foxk1 KO EBs. Bulk RNAseq analysis at two developmental stages showed a significant reduction of the cardiac molecular program in Foxk1 KO EBs compared to the control EBs. ATACseq analysis during EB differentiation demonstrated that the chromatin landscape nearby known important regulators of cardiogenesis was significantly relaxed in control EBs compared to Foxk1 KO EBs. Furthermore, we demonstrated that in the absence of FOXK1, cardiac differentiation was markedly impaired by assaying for cTnT expression and cardiac contractility. We demonstrate that FOXK1 is an important regulator of cardiogenesis by repressing the Wnt/β-catenin signaling pathway and thereby promoting differentiation. Conclusions These results identify FOXK1 as an essential transcriptional and epigenetic regulator of cardiovascular development. Mechanistically, FOXK1 represses Wnt signaling to promote the development of cardiac progenitor cells. Translational perspective Congenital heart disease is the most common birth defect. Deciphering the networks that govern cardiomyocyte specification, proliferation and differentiation will provide insights regarding therapeutic interventions for cardiovascular disease. The winged helix/forkhead family of transcription factors have been shown to have critical roles in epigenetics, organogenesis, cellular proliferation and differentiation. FOXK1 is an important transcription factor that regulates cardiovascular development through the Wnt signaling pathway. This FOXK1-Wnt pathway defines a network that may be therapeutically targeted to promote cardiogenesis.

Cognitive Impairment in Multiple Sclerosis

“…Given that mammalian forkhead transcription factors (FoxOs) can have an important relationship to cell death pathways during neurodegenerative disorders [2,5,49,259,260,[299][300][301][302][303][304], they are increasingly being recognized as potential therapeutic targets for MS (Figure 1). In particular, the mammalian FOXO proteins of the O class can lead to neuronal cell death through apoptosis and autophagy activation [5,49,50,68,128,203,250,301,[305][306][307][308][309][310][311][312][313][314][315].…”

Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

“…In particular, microglia are important for removing damaged cells during membrane PS externalization and apoptosis [106,131,145,277,278,298,308,[324][325][326][327]]. Yet, microglia can lead to the generation of oxidative stress through the production of ROS [8,165,167,246,250,[328][329][330][331], which can require modulation by non-coding RNAs [251,[332][333][334][335][336], Wnt signaling [27,28,106,115,276,[337][338][339], and trophic factor pathways with erythropoietin (EPO) [27,[340][341][342][343][344][345][346]. In other scenarios, microglial cells can be helpful for protection during amyotrophic lateral sclerosis [347], remove brain amyloid [348,349], and preserve cholesterol homeostasis with autophagy …”

“…Wnt signaling and WISP1 are vital pathways during metabolic disorders and DM for the oversight of oxidative stress, programmed cell death, and non-coding RNA function (Figure 2). Wnt proteins, which are cysteine-rich glycosylated proteins, are part of the wingless pathway that can modulate cell development and survival during aging, cardiovascular disorders, tumorigenesis, organogenesis, neurodegeneration, vascular disease, inflammation, and DM [25,28,48,76,92,115,131,150,184,276,296,297,305,307,338,339,[457][458][459][460][461][462][463][464][465][466][467]. Wnt proteins that can involve Wnt1 oversee programmed cell death [105,219,278,299,339,362,387,[467][468][469][470][471][472], pancreatic β-cell development and growth [473], skeletal function [152,305,307], trophic factor protec...…”

The role of epigenetic modifications in sensory hair cell development, survival, and regulation

“…Forkhead factors are well-known epigenetic regulators that can interacting with a chromatin remodeler or heterochromatin to relaxing the chromatin landscape. In cardiovascular development, FOXK1 could transcriptionally and epigenetically repressing Wnt signaling in cardiac progenitor cells, especially inhibit WNT6 expression ( Sierra-Pagan et al, 2023 ). The deletion of Kdm6a, an H3K27me3 demethylase, in chondrocytes inhibits the transcription of Wnt10a and Fzd10.…”