Arginine methylation provides epigenetic transcription memory for retinoid-induced differentiation in myeloid cells.
Cellular differentiation is governed by changes in gene expression, but at the same time, a cell's identity needs to be maintained through multiple cell divisions during maturation. In myeloid cell lines, retinoids induce gene expression and a well-characterized two-step lineage-specific differentiation. To identify mechanisms that contribute to cellular transcriptional memory, we analyzed the epigenetic changes taking place on regulatory regions of tissue transglutaminase, a gene whose expression is tightly linked to retinoid-induced differentiation. Here we report that the induction of an intermediary or "primed" state of myeloid differentiation is associated with increased H4 arginine 3 and decreased H3 lysine 4 methylation. These modifications occur before transcription and appear to prime the chromatin for subsequent hormone-regulated transcription. Moreover, inhibition of methyltransferase activity, pre-acetylation, or activation of the enzyme PAD4 attenuated retinoid-regulated gene expression, while overexpression of PRMT1, a methyltransferase, enhanced retinoid responsiveness. Taken together, our results suggest that H4 arginine 3 methylation is a bona fide positive epigenetic marker and regulator of transcriptional responsiveness as well as a signal integration mechanism during cell differentiation and, as such, may provide epigenetic memory.
Balint
Balint L
BL
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, University of Debrecen, Medical and Health Science Center, Nagyerdei krt. 98, Debrecen H-4012, Hungary.
Szanto
Attila
A
Madi
Andras
A
Bauer
Uta-Maria
UM
Gabor
Petra
P
Benko
Szilvia
S
Puskás
Laszlo G
LG
Davies
Peter J A
PJ
Nagy
Laszlo
L
D000107:Acetylation; D001120:Arginine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D018922:HL-60 Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D008954:Models, Biological; D022423:Myeloid Cells / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D014158:Transcription, Genetic; D011503:Transglutaminases / Q000378:metabolism
D002843:Chromatin; D005819:Genetic Markers; D006657:Histones; D007476:Ionophores; D012176:Retinoids; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; D011503:Transglutaminases; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases