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ACKNOWLEDGMENTS
We thank J. Michaud for theSim1+/−mice;M.J.Kimforthe
SCE2 hypothalamus picture; J. S. Weissman and S. Qi for the
dCas9-VP64 plasmids; B. Huang for theS. aureussgRNA vector;
C. Paillart for assistance with the metabolic profiling; S. K.
Matharu and Y. Ahituv for graphic assistance with the figures;
and M. T. McManus, P. Devine, and S. H. Ahanger for helpful
discussions.Funding:This article was supported in part by
grant 1R01DK090382 from the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK), the UCSF Nutrition
Obesity Research Center funded by National Institutes
of Health grant P30DK098722, and the UCSF School of Pharmacy
2017 Mary Anne Koda-Kimble Seed Award for Innovation. N.A.
is also supported by grants by the National Human Genome
Research Institute (NHGRI) and Division of Cancer Prevention,
National Cancer Institute grant no. 1R01CA197139, National
Institute of Mental Health grant no. 1R01MH109907, National
Institute of Child and Human Development 1P01HD084387, and
NHGRI grant no. 1UM1HG009408. N.M. was supported in part
by the UCSF School of Pharmacy 2017 Mary Anne Koda-Kimble
Seed Award for Innovation and the UCSF Catalyst Program.
S.R. was supported by the Royal Golden Jubilee Ph.D. Program
grant no. PHD/0071/2554. C.V. is also supported by NIDDK grant
nos. R01DK106404 and R01 DK60540-09 and Y.W. by theAmerican Diabetes Association Mentor Based Award-7-12-MN-79.
A.H. is supported by the National Institute of General Medical
Sciences IRACDA award K12GM081266.Author contributions:
N.M. and N.A. conceived and designed the study. N.M., S.T.,
and L.M. carried out the cloning and in vitro studies. N.M., S.R.,
S.T. and A.B. performed the mouse experiments. N.M. and
Y.W. carried out the immunostaining, and N.M. performed the
stereotactic surgeries and phenotypic analyses. A.H. and W.L.E.
helped in making fig. S1. W.L.E. carried out computational
analyses of genomic data; N.M., S.R., and N.A. analyzed the data;
C.V. and N.A. provided resources and critical suggestions; and
N.M. and N.A. wrote the manuscript.Competing interests:N.A.
is an equity holder of, and heads the scientific advisory board
for, Encoded Therapeutics, a gene regulation therapeutics company,
and N.A. and N.M. are cofounders of Enhancer Therapeutics Inc.
N.M. and N.A. are co-inventors on a patent (U.S. Patent
US2018017186) submitted by the University of California,
San Francisco, that covers gene therapy for haploinsufficiency.
Data and materials availability:All RNA-seq data were
deposited in NCBI as Bioproject PRJNA438712. All ChIP-seq data
were deposited in NCBI as Bioproject PRJNA438723.SUPPLEMENTARY MATERIALS
http://www.sciencemag.org/content/363/6424/eaau0629/suppl/DC1
Figs. S1 to S15
Tables S1 to S6
6 May 2018; accepted 6 December 2018
Published online 13 December 2018
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