Opposing LSD1 complexes function in developmental gene activation and repression programmes.
Precise control of transcriptional programmes underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies. One thing that remains unclear is how specific members of histone modification enzyme families, such as histone methyltransferases and demethylases, are used in vivo to simultaneously orchestrate distinct developmental gene activation and repression programmes. Here, we report that the histone lysine demethylase, LSD1--a component of the CoREST-CtBP co-repressor complex--is required for late cell-lineage determination and differentiation during pituitary organogenesis. LSD1 seems to act primarily on target gene activation programmes, as well as in gene repression programmes, on the basis of recruitment of distinct LSD1-containing co-activator or co-repressor complexes. LSD1-dependent gene repression programmes can be extended late in development with the induced expression of ZEB1, a Krüppel-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CoREST-CtBP co-repressor complex, causing repression of an additional cohort of genes, such as Gh, which previously required LSD1 for activation. These findings suggest that temporal patterns of expression of specific components of LSD1 complexes modulate gene regulatory programmes in many mammalian organs.
Wang
Jianxun
J
Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA.
Scully
Kathleen
K
Zhu
Xiaoyan
X
Cai
Ling
L
Zhang
Jie
J
Prefontaine
Gratien G
GG
Krones
Anna
A
Ohgi
Kenneth A
KA
Zhu
Ping
P
Garcia-Bassets
Ivan
I
Liu
Forrest
F
Taylor
Havilah
H
Lozach
Jean
J
Jayes
Friederike L
FL
Korach
Kenneth S
KS
Glass
Christopher K
CK
Fu
Xiang-Dong
XD
Rosenfeld
Michael G
MG
D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D013006:Growth Hormone / Q000235:genetics; D056466:Histone Demethylases; D018398:Homeodomain Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D052682:Lactotrophs / Q000378:metabolism; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D015533:Transcriptional Activation; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D013006:Growth Hormone; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating