TY - JOUR
T1 - A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation
AU - Laurent, Benoit
AU - Ruitu, Lv
AU - Murn, Jernej
AU - Hempel, Kristina
AU - Ferrao, Ryan
AU - Xiang, Yang
AU - Liu, Shichong
AU - Garcia, Benjamin A.
AU - Wu, Hao
AU - Wu, Feizhen
AU - Steen, Hanno
AU - Shi, Yang
N1 - Funding Information:
We thank members of the Shi lab for helpful discussions. In particular, we wish to thank James Lee (Dana Farber Cancer Institute, Boston) for help with the mass spectrometer and Angeles Fernandez-Gonzalez (Boston Children’s Hospital, Boston) for help with immunofluorescence microscopy. We thank Dr. Elizabeth J. Luna (University of Massachusetts Medical School, Worcester) for the pEGFP-SVIL constructs. B.L. was supported by fellowships from Association pour la Recherche sur le Cancer (ARC) and the Philippe Foundation. This work was supported by a grant from the NIH to Y.S. (R01 CA118487). Y.S. is an American Cancer Society Research Professor.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/3/19
Y1 - 2015/3/19
N2 - Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.
AB - Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.
UR - http://www.scopus.com/inward/record.url?scp=84925199744&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2015.01.010
DO - 10.1016/j.molcel.2015.01.010
M3 - Article
C2 - 25684206
AN - SCOPUS:84925199744
SN - 1097-2765
VL - 57
SP - 957
EP - 970
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -