TY - JOUR
T1 - Histone Variant MacroH2A1 Plays an Isoform-Specific Role in Suppressing Epithelial-Mesenchymal Transition
AU - Hodge, Dayle Q.
AU - Cui, Jihong
AU - Gamble, Matthew J.
AU - Guo, Wenjun
N1 - Funding Information:
We thank John Christin and Alyssa Casill for technical help. We thank the Analytical Imaging facility of Albert Einstein College of Medicine (supported by Einstein Cancer Center support grant P30 CA013330) and the New York State Department of Health (NYSTEM Program) for shared facility grant support (C029154). This work is supported by grants from DOD BRCP (W81XWH-16–1–0311), Susan Komen for the Cure (CCR12224440), and the V Foundation for Cancer Research. W.G. is a V Scholar. D.Q.H. was supported by the Medical Scientist Training Program of the Albert Einstein College of Medicine (NIH T32-GM007288).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Epithelial-Mesenchymal Transition (EMT) is a biological program that plays key roles in various developmental and pathological processes. Although much work has been done on signaling pathways and transcription factors regulating EMT, the epigenetic regulation of EMT remains not well understood. Histone variants have been recognized as a key group of epigenetic regulators. Among them, macroH2A1 is involved in stem cell reprogramming and cancer progression. We postulated that macroH2A1 may play a role in EMT, a process involving reprogramming of cellular states. In this study, we demonstrate that expression of macroH2A1 is dramatically reduced during EMT induction in immortalized human mammary epithelial cells (HMLE). Moreover, ectopic expression of the macroH2A1.1 isoform, but not macroH2A1.2, can suppress EMT induction and reduce the stem-like cell population in HMLE. Interestingly, macroH2A1.1 overexpression cannot revert stable mesenchymal cells back to the epithelial state, suggesting a stage-specific role of macroH2A1.1 in EMT. We further pinpointed that the function of macroH2A1.1 in EMT suppression is dependent on its ability to bind the NAD+ metabolite PAR, in agreement with the inability to suppress EMT by macroH2A1.2, which lacks the PAR binding domain. Thus, our work discovered a previously unrecognized isoform-specific function of macroH2A1 in regulating EMT induction.
AB - Epithelial-Mesenchymal Transition (EMT) is a biological program that plays key roles in various developmental and pathological processes. Although much work has been done on signaling pathways and transcription factors regulating EMT, the epigenetic regulation of EMT remains not well understood. Histone variants have been recognized as a key group of epigenetic regulators. Among them, macroH2A1 is involved in stem cell reprogramming and cancer progression. We postulated that macroH2A1 may play a role in EMT, a process involving reprogramming of cellular states. In this study, we demonstrate that expression of macroH2A1 is dramatically reduced during EMT induction in immortalized human mammary epithelial cells (HMLE). Moreover, ectopic expression of the macroH2A1.1 isoform, but not macroH2A1.2, can suppress EMT induction and reduce the stem-like cell population in HMLE. Interestingly, macroH2A1.1 overexpression cannot revert stable mesenchymal cells back to the epithelial state, suggesting a stage-specific role of macroH2A1.1 in EMT. We further pinpointed that the function of macroH2A1.1 in EMT suppression is dependent on its ability to bind the NAD+ metabolite PAR, in agreement with the inability to suppress EMT by macroH2A1.2, which lacks the PAR binding domain. Thus, our work discovered a previously unrecognized isoform-specific function of macroH2A1 in regulating EMT induction.
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U2 - 10.1038/s41598-018-19364-4
DO - 10.1038/s41598-018-19364-4
M3 - Article
C2 - 29339820
AN - SCOPUS:85040812636
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 841
ER -
