REST regulatory networks Gene Yeo1,2 Stefan Aigner 2,

REST regulatory networks Gene Yeo1,2 Stefan Aigner 2, Eric Van Nostrand1,2, Fred H. Gage2 1 Crick-Jacobs Center of Theoretical and Computational Biology 2 Laboratory of Genetics The Salk Institute for Biological Studies, La Jolla, CA REST repressor/silencing complex silences neuronal genes in non-neuronal cells Differentiated non-neuronal cells m mK9 mCpG Methyl H3K9 MeCP2 HDAC mSin3

SCP CoREST DNMT1 HMT K9 REST mK9 m m mK9 mK9 m mK9 m RE1 m

m Histone K4 Demethylase HDAC mK9 MeCP2 m m HP1 mK9 mK9 m mK9 REST binds to a ~20 bp sequence REST levels decrease during neuronal differentiation

Slide courtesy of XC REST sites are highly-conserved across evolution Superiorcervical ganglion neuralspecific 10 Synaptosomalassociated protein 25 Brain-derived neurotrophic factor Algorithm to identify conserved REST sites Converged motif Several REST sites are proximal to microRNAs REST-regulated microRNAs are neuronal REST binds in vivo to predicted sites

REST occupancy near microRNA genes decreases during neural differentiation Anti-REST chromatin immunoprecipitation/qPCR for candidate REST sites in P19 cells upon neural induction 0.8 0.7 0.6 Undifferentiated Differentiated 0.5 0.4 0.3 0.2 0.1 0 % of chromatin immunoprecipitated miR-9-3 30e/30c-1 miR135b miR153-1 miR-29a/29b-1 miR219-1 miR192/194-2 miR182/96/183

Neural-specific microRNAs and REST co-repressors during mouse stem cell neuronal differentiation Neural differentiation of P19 mouse embryonic carcinoma cells RA induction Western blots Northern blots d0 d5 d7 d9 d11 miR-9 miR-124a U6 d0 d5 d7 d9 d11 REST msin3A SCP-1 CoREST Neuronal marker TUJ1

Neural-specific microRNAs likely target components of the REST co-repressor complex Plasmid transfected: GFP m mK9 mCpG Plasmid transfected: empty mir-9 msin3A SCP-1 -actin Loading control

em pt m y ir3 m 24 ir1 m ir1 24 mir-9 and mir-124a downregulate mSin3a and SCP-1, respectively Methyl H3K9 MeCP2 HDAC mSin3 HDAC SCP REST

mK9 m m mK9 mK9 m mK9 m RE1 m m Histone K4 Demethylase mK9

CoREST DNMT1 HMT K9 HP1 MeCP2 m m mK9 mK9 m mK9 Neural-specific microRNAs likely target components of the REST corepressor complex A sensor assay confirms predicted target sites for miR-124a in the 3UTR of SCP-1 SCP-1 3UTR SCP-1 sensor ADAR1 3UTR

Control sensor Control sensor SCP1 sensor + mir124 Enhancing neurogenesis mir-124 induces neuronal gene expression in P19 mouse EC cells 6 5 4 24 hours 48 hours 3 2 change Fold (mir124/control) 1

0 GAP43 NFH Glur2 Promoter driving luciferase ND1 A model for REST regulation to enhance neurogenesis Neuronal progenitors REST high Neurons REST low REST-regulated microRNAs ON REST-regulated microRNAs

downregulate components of the REST repressor complex REST-regulated microRNAs OFF REST-regulated protein coding genes OFF Acknowledgements: Eunice Meija, Xinwei Cao REST-regulated protein coding genes ON Supported by Crick-Jacobs Center, NSF

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