Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcription factor NFYa controls cardiomyocyte metabolism and proliferation during fetal heart development [ChIP-seq]

ABSTRACT: Cardiomyocytes are highly metabolic cells responsible for generating the contractile force that drives heart function. During fetal development and regeneration, these cells undergo active division but lose their proliferation activity in the adult heart. The mechanisms that coordinate their metabolism and proliferation are not fully understood. Here, we study the developmental functions of the transcription factor NFYa, which we previously identified from regenerating cardiomyocytes. We show that loss of NFYa profoundly alters cardiomyocyte composition, with a decrease in immature regenerative cells and an increase in trabecular and mature cardiomyocytes, as revealed by spatial and single-cell transcriptome analyses. NFYa-deleted cardiomyocytes exhibited reduced proliferation and impaired mitochondrial metabolism, contributing to the cardiac growth defect. NFYa acts as a transcriptional activator of mitochondrial metabolic genes as well as cell-cycle genes in cardiomyocytes through its interaction with the cofactor SP2, providing a direct link between metabolism and proliferation at the gene transcriptional level. Our study reveals a key role of NFYa in regulating cardiac growth before birth and a previously unrecognized transcriptional control mechanism of metabolic genes in the heart, and highlights the importance of mitochondrial metabolism during fetal heart development and regeneration.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE232960 | GEO | 2023/10/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcription factor NFYa controls cardiomyocyte metabolism and proliferation during fetal heart development [Visium]

Project description:Cardiomyocytes are highly metabolic cells responsible for generating the contractile force that drives heart function. During fetal development and regeneration, these cells undergo active division but lose their proliferation activity in the adult heart. The mechanisms that coordinate their metabolism and proliferation are not fully understood. Here, we study the developmental functions of the transcription factor NFYa, which we previously identified from regenerating cardiomyocytes. We show that loss of NFYa profoundly alters cardiomyocyte composition, with a decrease in immature regenerative cells and an increase in trabecular and mature cardiomyocytes, as revealed by spatial and single-cell transcriptome analyses. NFYa-deleted cardiomyocytes exhibited reduced proliferation and impaired mitochondrial metabolism, contributing to the cardiac growth defect. NFYa acts as a transcriptional activator of mitochondrial metabolic genes as well as cell-cycle genes in cardiomyocytes through its interaction with the cofactor SP2, providing a direct link between metabolism and proliferation at the gene transcriptional level. Our study reveals a key role of NFYa in regulating cardiac growth before birth and a previously unrecognized transcriptional control mechanism of metabolic genes in the heart, and highlights the importance of mitochondrial metabolism during fetal heart development and regeneration.

2023-10-13 | GSE232962 | GEO

Transcription factor NFYa controls cardiomyocyte metabolism and proliferation during fetal heart development [Multiome]

2023-10-13 | GSE232961 | GEO

Transcriptome profiling of neonatal rat ventricular cardiomyocytes overexpressing NFYa or NFE2L1

Project description:The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart has a transient ability to regenerate, however the molecular mechanism that mediates this regenerative response is not fully understood. Here, by single-nucleus RNA sequencing we map the transcriptome landscape of cardiomyocytes in neonatal mouse hearts at healthy, regenerative, and remodeling conditions. We show that an immature cardiomyocyte population enters cell-cycle in response to injury. Absence of this cardiomyocyte population overtime is associated with the loss of the ability of the heart to regenerate. We show a defined injury response in these cardiomyocytes, including activation of transcription factors NFYa and NFE2L1, which play proliferative and protective roles, respectively. We further show that overexpression of these two factors in vivo promotes heart regeneration. Thus, these findings refined our understanding of cellular basis of neonatal heart regeneration and reveal dynamic transcriptome landscape of cardiomyocytes in response to injury.

2020-03-18 | GSE142364 | GEO

Single-cell analysis uncovers that metabolic reprogramming is essential for cardiomyocyte proliferation in the regenerating heart.

Project description:While the heart regenerates poorly in mammals, efficient heart regeneration occurs in certain amphibian and fish species. Zebrafish has been used extensively to study heart regeneration, resulting in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. However, there is limited knowledge about the cellular processes that occur in this rare population of proliferating cardiomyocytes during heart regeneration. To identify such processes, we generated a transgenic line based on nppa expression that marks proliferating cardiomyocytes located at the wound border zone. Next we have used a single-cell RNA-sequencing approach in the regenerating adult zebrafish heart and we uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the non-proliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial oxidative phosphorylation activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Mechanistically, this metabolic reprogramming is induced by Nrg1/Erbb2 signaling and this mechanism is conserved in murine hearts. Furthermore, pharmacological inhibition of glycolysis impairs cardiomyocyte proliferation of both zebrafish and murine cardiomyocytes. Together these results reveal a conserved mechanism in which cardiomyocytes undergo metabolic reprogramming, which is essential for cardiomyocyte proliferation and heart regeneration and could ultimately help to develop novel methods to promote mammalian heart repair.

2019-12-24 | GSE139218 | GEO

Amino acid priming of mTOR is essential for heart regeneration

Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.

2022-02-15 | PXD011791 | Pride

Amino acid primed mTOR activity is essential for heart regeneration [bulk RNA-seq]

Project description:Heart disease is the leading cause of death as there is no current method to repair damaged myocardium due to the limited proliferative capacity of adult cardiomyocytes. Curiously, mouse neonates and zebrafish, larvae or adult, are able to regenerate their hearts via cardiomyocyte de-differentiation and proliferation. However, a molecular mechanism of why these cardiomyocytes can re-enter cell cycle is poorly understood. Here, we identify a unique metabolic state that primes adult zebrafish and neonatal mouse ventricular cardiomyocytes to proliferate. Zebrafish and neonatal mouse hearts display elevated glutamine levels, predisposing them to amino acid-driven activation of TOR. We show that this TOR activation is required for zebrafish cardiomyocyte regeneration in vivo. After injury we observe pS6 in both the epicardium and ventricular cardiomyocytes suggesting these are amino acid primed cells necessary for regeneration. Through single cell and system-wide RNA-sequencing, LQC proteomics and microscopy we identify dramatic metabolic and mitochondrial changes during the first week of regeneration. These data suggest that regeneration of zebrafish myocardium is driven by metabolic remodeling and reveals a unique metabolic regulator, TOR-primed state, in which zebrafish and mammalian cardiomyocytes are regeneration competent.

2022-01-11 | GSE188243 | GEO

Amino acid primed mTOR activity is essential for heart regeneration [scRNA-seq]

2022-01-11 | GSE184914 | GEO

Knockdowns of total NFYA and a NFYA long 3’ UTR isoform followed by RNA-seq to determine isoform-specific effects on gene expression

Project description:Alternative cleavage and polyadenylation (APA) produces multiple isoforms of the Nuclear Transcription Factor Y Subunit Alpha (NFYA) gene with variable length 3? untranslated regions (UTRs). These isoforms have been detected in HCT116 colon cancer cells via polyA-seq and northern blots, as well as colon cancer tissue RNA-seq data. NFYA is a transcription factor that may regulate cell growth and proliferation in cancer and development. To determine if there may be transcriptional regulation unique to the long 3’ UTR isoform, we conducted an siRNA knockdown in HCT116 cells specific to either the long isoform (by targeting sequence uniquely present in the longer transcript) or total NFYA mRNA (by targeting sequence shared by all long and short NFYA mRNA isoforms) followed by next generation sequencing of RNA (RNA-seq) to analyze the transcriptome.

2022-12-28 | GSE86179 | GEO

Single cell ATAC-seq of cardiomyocytes from neonatal mouse hearts after injury

2020-03-18 | GSE142365 | GEO

Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish

Project description:Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.

2020-07-13 | PXD016235 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data