Histone deacetylase 1 deficiency impairs differentiation and electrophysiological properties of cardiomyocytes derived from induced pluripotent cells.
Epigenetic and chromatin modifications play particularly important roles in embryonic and induced pluripotent stem cells (ESCs and iPSCs) allowing for the cells to both differentiate and dedifferentiate back to a pluripotent state. We analyzed how the loss of a key chromatin-modifying enzyme, histone deacetylase 1 (HDAC1), affects early and cardiovascular differentiation of both ESCs and iPSCs. We also investigated potential differences between these two cell types when differentiation is induced. Our data indicate an essential role for HDAC1 in deacetylating regulatory regions of key pluripotency-associated genes during early differentiation. Although HDAC1 functions primarily as a HDAC, its loss also affects DNA methylation in ESCs and iPSCs both during pluripotency and differentiation. We show that HDAC1 plays a crucial, nonredundant role in cardiomyocyte differentiation and maturation. Our data also elucidate important differences between ESCs and iPSCs, when levels of this enzyme are reduced, that affect their ability to differentiate into functional cardiomyocytes. As varying levels of chromatin-modifying enzymes are likely to exist in patient-derived iPSCs, understanding the molecular circuitry of these enzymes in ESCs and iPSCs is critical for their potential use in cardiovascular therapeutic applications
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Eneda
E
Hoxha
Erin
E
Lambers
Hehuang
H
Xie
Alexandre
A
De Andrade
Prasanna
P
Krishnamurthy
John A
JA
Wasserstrom
Veronica
V
Ramirez
Melissa
M
Thal
Suresh K
SK
Verma
Marcelo B
MB
Soares
Raj
R
Kishore
D000818:Animals; D020013:Calcium Signaling; D002454:Cell Differentiation; D018031:Connexin 43 / Q000378:metabolism; D019175:DNA Methylation; D058732:Embryoid Bodies / Q000201:enzymology / Q000502:physiology; D044127:Epigenesis, Genetic; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000172:deficiency / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology*; D041681:NIH 3T3 Cells; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics; D017422:Sequence Analysis, DNA; D020107:Troponin T / Q000235:genetics / Q000378:metabolism
D018031:Connexin 43; C543076:GJA1 protein, mouse; D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D034741:RNA, Small Interfering; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D020107:Troponin T; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1