Epigenetic complexities at the heart of 15q11-13

15q noncoding RNAs involved in topotecan action and diurnal metabolism

Janine M. LaSalle, Ph.D UC Davis School of Medicine MIND Instute Genome Center 15q duplications: the interesting case of too many maternal copies Does copy number correlate with copy number of 15q11-13 in Dup15q syndrome?

only for UBE3A*, not GABRB3 or SNRPN

Snrpn levels inversely correlate with 15q copy number Heterogeneity between 8 individual postmortem samples potentially explains heterogeneity in PWS-like phenotypes in Dup15q syndrome Scoles et al, 2010 A neuronal Dup15q cell culture model recapitulates transcription defects of Dup15q brain samples

Meguro-Horike et al, 2011 Epigenetics: long-lived and reversible modifications to nucleotides or chromosomes that do not change the sequence but can alter gene expression and phenotype

Parental imprinting: epigenetic modifications differentially inherited from the gametes (egg versus sperm) that silence gene expression in a parental specific pattern

Epigenec layers and players acng at 15q11-13 Layers Players DNA methylaon MeCP2 Histone modificaons ATRX, CTCF, Cohesin Chroman loops DNA methyltransferases Spaal nuclear organizaon Histone methyltransferases Noncoding RNAs Histone demethylases Histone acetylases Histone deacetylases DNA methylation and histone marks of parental imprinting at 15q11-q13

H3 K4me

MeCP2 ATRX

H3 K9me Chromosome Bands Localized by FISH Mapping Clones Chromosome Band 15q11.2 15q12 15q13.1 15q13.2 15q13.3 15q14 Duplications of >1000 Bases of Non-RepeatMasked Sequence Segmental Dups placentaPercentMethylationchr15 PercMethylationchr15 PlacentaPartialMethylation entaPartialMethylation IMRPartialMethylation30 RPartialMethylation30 SHPartialMethylation30 HPartialMethylation30 UCSC Genes (RefSeq, GenBank, tRNAs & Comparative Genomics) DQ592463 POTEB OR4M2 CYFIP1 FLJ36144 AK124131 SNRPN AX747189 GABRB3 OCA2 AK309255 hXllL TJP1 BC117556 TRPM1 CHRNA7-2 SCG5 RYR3 DQ570464 AK311417 CR622584 A26B1 OR4N4 CYFIP1 FLJ36144 AK058147 HBT8 ATP10A GABRB3 OCA2 AK307870 NDNL2 TJP1 BC117556 MLSN1 CHRNA7-2 SCG5 RYR3 DQ585295 LOC723972 HERC2P3 DQ786202 CYFIP1 MKRN3 BC034815 IPW ATP10C GABRB3 DKFZp547P028 BC047911 BC043570 DQ786262 TRPM1 CHRNA7 DRM AVEN GJD2 ATPBD4 HERC2P3 AK058056 CYFIP1 MKRN3 C15orf2 IPW BC038777 GABRA5 HERC2 BC018626 TJP1 FLJ00278 TRPM1 CHRNA7 GREM1 CHRM5 AK092087 ATPBD4 BC012949 BC062994 CYFIP1 MKRN3 SNRPN GABRB3 HERC2 BC035099 TJP1 DQ582641 DJ022684 CHRNA7 GREM1 CHRM5 ACTC1 ATPBD4 AX748135 OR4N4 NIPA2 MAGEL2 SNRPN AK124673 HERC2 APBA2 AK310526 DQ599399 KLF13 CHRNA7 FMN1 CHRM5 AQR DQ582073 OR4N4 NIPA2 NDN SNRPN GABRG3 HERC2 APBA2 DQ592322 DQ600342 OTUD7A DQ585996 FMN1 C15orf24 LOC643007 DQ595648 LOC650137 NIPA2 SNRPN GABRG3 FLJ36131 APBA2 DQ582940 DQ582940 OTUD7A BC117556 FMN1 ORF3 ZNF770 GOLGA8E CR619482 NIPA2 SNURF LOC283767 KIAA0574 DQ578838 DQ588973 Cezanne 2 BC037839 PGBD4 BC069776 DQ592322 AJ004954 NIPA2 SNRPN GOLGA8G KIAA0574 CHRFAM7A AK093758 CHRNA7 C15orf29 ZNF770 DQ578838 IGH NIPA2 SNRPN FLJ32679 DQ595055 DQ595055 Cezanne 2 AK310041 TMEM85 DQ582025 IGH NIPA1 SNRPN GOLGA8G DQ572986 DQ572986 CHRFAM7A TMEM85 AL832227 GOLGA8E BC012949 SNURF DQ592322 DQ575284 MTMR15 CHRNA7 TMEM85 DQ582260 GOLGA8E FLJ36131 SNRPN DQ578838 DQ577333 MTMR15 CHRFAM7A TMEM85 DQ582260 DQ582025 DQ582073 SNURF DQ583954 DQ578370 KIAA1018 CHRFAM7A SLC12A6 M84131 DQ582940 GOLGA8E AF319524 GOLGA8G DQ573498 MTMR15 DQ786280 SLC12A6 BC047459 DQ599733 DQ592322 SNORD107 FLJ32679 DQ597873 MTMR15 DKFZp434L187 SLC12A6 DQ786202 LOC283767 DQ578838 SNORD108 GOLGA8G DQ596319 MTMR10 DKFZp434L187 SLC12A6 DQ582071 DQ582025 SNORD109B DQ579249 DQ596303 MTMR10 DQ595740 SLC12A6 TUBGCP5 AX748135 SNORD116-1 DQ599733 DQ575742 MTMR10 DQ578707 SLC12A6 TUBGCP5 DQ582073 DKFZp686M12165 LOC283767 DQ590322 MTMR10 DQ593033 SLC12A6 KIAA1899 LOC283767 SNORD116-2 DQ594306 BC070492 MTMR10 BC070492 SLC12A6 NIPA1 AY362862 FLJ36131 BC071630 MTMR10 DQ599733 SLC12A6 NIPA1 SNORD116-3 DQ582071 BC071855 BC023564 SLC12A6 BC044583 DKFZp686M12165 AK311660 AK310526 BC071630 SLC12A6 WHAMML1 DKFZp686M12165 AK095014 DQ600342 BC062414 SLC12A6 WHAMML1 SNORD116-4 AK095014 DQ578838 DQ587888 NOP10 WHAMML1 SNORD116-5 DQ582025 DQ583692 DQ575742 C15orf55 WHAMML1 SNORD116-2 DQ571064 DQ572979 DQ573819 LPCAT4 AX747926 SNORD116-5 DQ588687 DQ590616 DQ596319 LPCAT4 DQ600343 SNORD116-8 DQ582940 DQ593239 DQ585295 GOLGA8B DQ582940 SNORD116-3 DQ597560 DKFZp434L187 DQ573497 GOLGA8B DQ578838 SNORD116-10 BC150525 DKFZp434L187 DQ583847 GOLGA8A DQ588972 SNORD116-11 BC150524 CHRFAM7A DQ599785 GOLGA8A DQ583692 SNORD116-12 BC066982 CHRFAM7A DQ578707 DQ571064 DQ572986 SNORD116-13 AK091254 CHRFAM7A LOC643699 DQ582940 KIAA0393 SNORD116-14 DQ587888 DQ582688 GOLGA8B KIAA0393 DKFZp686M12165 DQ578300 FLJ00278 GOLGA8A Genomic scale DNA methylaon and histone modificaon landscape of 15q KIAA0393 SNORD116-15 DQ596319 DQ597780 GOLGA8B KIAA0393 SNORD116-16 DQ585847 FLJ00278 DQ582688 KIAA0393 DKFZp686M12165 DQ583847 LOC643699 Neuronal highly methylated (N-HMDs) and parally methylated (PMDs) domains on 15q11-14 DQ594309 SNORD116-19 DQ599785 DQ595055 DQ595648 DKFZp686M12165 DQ575242 DQ572985 DQ600342 SNORD116-18 DQ582448 ARHGAP11A DQ578838 SNORD116-19 LOC643699 Schroeder et al, 2011; Schroeder et al, 2013 ARHGAP11A DQ572979 SNORD116-20 Chromosome Bands Localized by FISH Mapping Clones DQ598729 ARHGAP11A Chromosome Band 15q11.2 SNORD116-22 15q12 15q13.1 FLJ0027815q13.2 15q13.3C15orf45 15q14 SNORD116-23 Duplications of >1000 Bases of Non-RepeatMasked Sequence BC037839 AX747968 Segmental Dups BP1 BP2 C15orf49 BP3 DQ595055BP4 BP5 SNORD116-24 placentaPercentMethylationchr15 DQ575284 PercMethylationchr15 SNORD116-25 DQ577333 SNORD116-26 PlacentaPartialMethylation DQ593239 entaPartialMethylation SNORD116-27 DQ596319 SNORD116-28 IMRPartialMethylation30 DQ596303 RPartialMethylation30 SNORD116-29 DQ590322 AF400490 SHPartialMethylation30 BC062414 HPartialMethylation30 PAR1 BC070492 SNORD115-1 UCSC Genes (RefSeq, GenBank, tRNAs & Comparative Genomics) BC071630 DQ592463 POTEB OR4M2 CYFIP1 FLJ36144 AK124131 SNRPNSNORD115-2 AX747189 GABRB3 OCA2 AK309255 hXllL TJP1 BC117556BC071855 TRPM1 CHRNA7-2 SCG5 RYR3 DQ570464 AK311417 CR622584 A26B1 OR4N4 CYFIP1 FLJ36144 AK058147 AF400491HBT8 ATP10A GABRB3 OCA2 AK307870 NDNL2 TJP1 BC117556DQ600342 MLSN1 CHRNA7-2 SCG5 RYR3 DQ585295 LOC723972 HERC2P3 DQ786202 CYFIP1 MKRN3 BC034815SNORD115-3IPW ATP10C GABRB3 DKFZp547P028 BC047911 BC043570 DQ786262AK310030 TRPM1 CHRNA7 DRM AVEN GJD2 ATPBD4 HERC2P3 AK058056 CYFIP1 MKRN3 C15orf2SNORD115-4IPW BC038777 GABRA5 HERC2 BC018626 TJP1 ARHGAP11BFLJ00278 TRPM1 CHRNA7 GREM1 CHRM5 AK092087 ATPBD4 BC012949 BC062994 CYFIP1 MKRN3 SNRPNSNORD115-5 GABRB3 HERC2 BC035099 TJP1 ARHGAP11BDQ582641 DJ022684 CHRNA7 GREM1 CHRM5 ACTC1 ATPBD4 AX748135 OR4N4 NIPA2 MAGEL2 SNRPNAF400492 AK124673 HERC2 APBA2 AK310526ARHGAP11BDQ599399 KLF13 CHRNA7 FMN1 CHRM5 AQR DQ582073 OR4N4 NIPA2 NDN SNRPNSNORD115-6 GABRG3 HERC2 APBA2 DQ592322 MGC131512DQ600342 OTUD7A DQ585996 FMN1 C15orf24 LOC643007 DQ595648 LOC650137 NIPA2 SNRPNAY362864 GABRG3 FLJ36131 APBA2 DQ582940 DQ582940 OTUD7A BC117556 FMN1 ORF3 ZNF770 GOLGA8E CR619482 NIPA2 SNORD115-7SNURF LOC283767 KIAA0574 DQ578838 DQ588973 Cezanne 2 BC037839 PGBD4 BC069776 DQ592322 AJ004954 NIPA2 SNRPNAF400493 GOLGA8G KIAA0574 CHRFAM7A AK093758 CHRNA7 C15orf29 ZNF770 DQ578838 IGH NIPA2 SNORD115-8SNRPN FLJ32679 DQ595055 DQ595055 Cezanne 2 AK310041 TMEM85 DQ582025 IGH NIPA1 SNORD115-5SNRPN GOLGA8G DQ572986 DQ572986 CHRFAM7A TMEM85 AL832227 GOLGA8E BC012949 SNORD115-10SNURF DQ592322 DQ575284 MTMR15 CHRNA7 TMEM85 DQ582260 GOLGA8E FLJ36131 SNORD115-11SNRPN DQ578838 DQ577333 MTMR15 CHRFAM7A TMEM85 DQ582260 DQ582025 DQ582073 SNURFAY362865 DQ583954 DQ578370 KIAA1018 CHRFAM7A SLC12A6 M84131 DQ582940 GOLGA8E AF319524SNORD115-5 GOLGA8G DQ573498 MTMR15 DQ786280 SLC12A6 BC047459 DQ599733 DQ592322 SNORD107SNORD115-13 FLJ32679 DQ597873 MTMR15 DKFZp434L187 SLC12A6 DQ786202 LOC283767 DQ578838 SNORD108SNORD115-14 GOLGA8G DQ596319 MTMR10 DKFZp434L187 SLC12A6 DQ582071 DQ582025 SNORD109BAF400497 DQ579249 DQ596303 MTMR10 DQ595740 SLC12A6 TUBGCP5 AX748135 SNORD116-1AF400498 DQ599733 DQ575742 MTMR10 DQ578707 SLC12A6 TUBGCP5 DQ582073 DKFZp686M12165SNORD115-15 LOC283767 DQ590322 MTMR10 DQ593033 SLC12A6 KIAA1899 LOC283767 SNORD116-2SNORD115-16 DQ594306 BC070492 MTMR10 BC070492 SLC12A6 NIPA1 SNORD115-17AY362862 FLJ36131 BC071630 MTMR10 DQ599733 SLC12A6 NIPA1 SNORD116-3SNORD115-17 DQ582071 BC071855 BC023564 SLC12A6 BC044583 DKFZp686M12165SNORD115-17 AK311660 AK310526 BC071630 SLC12A6 WHAMML1 DKFZp686M12165SNORD115-20 AK095014 DQ600342 BC062414 SLC12A6 WHAMML1 SNORD116-4SNORD115-22 AK095014 DQ578838 DQ587888 NOP10 WHAMML1 SNORD116-5SNORD115-23 DQ582025 DQ583692 DQ575742 C15orf55 WHAMML1 SNORD116-2AF400499 DQ571064 DQ572979 DQ573819 LPCAT4 AX747926 SNORD116-5HBII-52-24 DQ588687 DQ590616 DQ596319 LPCAT4 DQ600343 SNORD116-8SNORD115-25 DQ582940 DQ593239 DQ585295 GOLGA8B DQ582940 SNORD116-3AF400501 DQ597560 DKFZp434L187 DQ573497 GOLGA8B DQ578838 SNORD116-10SNORD115-26 BC150525 DKFZp434L187 DQ583847 GOLGA8A DQ588972 SNORD116-11HBII-52-27 BC150524 CHRFAM7A DQ599785 GOLGA8A DQ583692 SNORD116-12HBII-52-28 BC066982 CHRFAM7A DQ578707 DQ571064 DQ572986 SNORD116-13SNORD115-11 AK091254 CHRFAM7A LOC643699 DQ582940 KIAA0393 SNORD116-14SNORD115-30 DQ587888 DQ582688 GOLGA8B KIAA0393 DKFZp686M12165SNORD115-31 DQ578300 FLJ00278 GOLGA8A KIAA0393 SNORD116-15SNORD115-32 DQ596319 DQ597780 GOLGA8B KIAA0393 SNORD116-16SNORD115-33 DQ585847 FLJ00278 DQ582688 KIAA0393 DKFZp686M12165SNORD115-35 DQ583847 LOC643699 DQ594309 SNORD116-19SNORD115-11 DQ599785 DQ595055 DQ595648 DKFZp686M12165AF400501 DQ575242 DQ572985 DQ600342 SNORD116-18SNORD115-37 DQ582448 ARHGAP11A DQ578838 SNORD116-19SNORD115-38 LOC643699 ARHGAP11A DQ572979 SNORD116-20SNORD115-39 DQ598729 ARHGAP11A SNORD116-22SNORD115-40 FLJ00278 C15orf45 SNORD116-23SNORD115-41 BC037839 AX747968 SNORD115-10C15orf49 DQ595055 SNORD116-24SNORD115-11 DQ575284 SNORD116-25SNORD115-44 DQ577333 SNORD116-26HBII-52-45 DQ593239 SNORD116-27AF400500 DQ596319 SNORD116-28HBII-52-46 DQ596303 SNORD116-29SNORD115-48 DQ590322 AF400490SNORD109B BC062414 PAR1UBE3A BC070492 SNORD115-1UBE3A BC071630 SNORD115-2UBE3A BC071855 AF400491UBE3A DQ600342 SNORD115-3UBE3A AK310030 SNORD115-4 ENCODE Chromatin State Segmentation by HMM from Broad Institute, MIT and MGHARHGAP11B GM12878 ChromHMM SNORD115-5 ARHGAP11B H1-hESC ChromHMM AF400492 ARHGAP11B HUVEC ChromHMM SNORD115-6 MGC131512 HSMM ChromHMM AY362864 NHEK ChromHMM SNORD115-7 NHLF ChromHMM AF400493 SNORD115-8 SNORD115-5 SNORD115-10 SNORD115-11 AY362865 SNORD115-5 SNORD115-13 SNORD115-14 AF400497 AF400498 SNORD115-15 SNORD115-16 SNORD115-17 SNORD115-17 SNORD115-17 SNORD115-20 SNORD115-22 SNORD115-23 AF400499 HBII-52-24 SNORD115-25 AF400501 SNORD115-26 HBII-52-27 HBII-52-28 SNORD115-11 SNORD115-30 SNORD115-31 SNORD115-32 SNORD115-33 SNORD115-35 SNORD115-11 AF400501 SNORD115-37 SNORD115-38 SNORD115-39 SNORD115-40 SNORD115-41 SNORD115-10 SNORD115-11 SNORD115-44 HBII-52-45 AF400500 HBII-52-46 SNORD115-48 SNORD109B UBE3A UBE3A UBE3A UBE3A UBE3A ENCODE Chromatin State Segmentation by HMM from Broad Institute, MIT and MGH GM12878 ChromHMM H1-hESC ChromHMM HUVEC ChromHMM HSMM ChromHMM NHEK ChromHMM NHLF ChromHMM Figure'4.'Three'sub.layers'of'chroma6n'loop'interac6onsChromatin loops and! long-range chromatin dynamics at 15q

A. Enhancer-promoter 7 Kb B. Topological domain 700 Kb Long-range chroman dynamics at 15q

Arc neuron specific C. Long range looping CTCF CTCF 7 Mb postnatal specific allele-specific (imprinted)

HoxA cohesin

CTCF ? MeCP2 MeCP2

LaSalle, Powell, Yasui, TINS 2013 PWS-IC CHRNA7

4C Chromatin decondensation FISH HBII85 SNRPN

mature neurons

immature neurons

Leung et al, 2009; Yasui et al, 2011; Meguro et al, 2011 The commonality of long noncoding RNAs at imprinted loci with tissue-specific imprinting

Chromosome 15: SNRPN-UBE3A locus SNORD116/ SNORD115/1 MKRN3 MAGEL2 NDN SNRPN 116HG 15HG

UBE3A* Chromosome 7: IGF2 locus IGF2 INS2*

Paternal allele IGF2-AS Maternal allele H19 lncRNA Unmethylated DMR Methylated DMR Chromosome 16: IGF2R locus Imprinted protein-coding gene AIRN lncRNA Imprinted lncRNA * Tissue-specific imprinng

IGF2R Chromosome 7: KCNQ1 locus KCNQ1OT1lncRNA

ASCL2* TSPAN32* CD81* KCNQ1 Paternal SNRPN-UBE3A neuronal transcript encompasses the minimal deleon region for PWS

Detected only in neurons

PWS-IC PWS small deletions

UBE3A

• Minimal deletion causing Prader-Willi Syndrome maps to the repetitive region encoding the snoRNA SNORD116 (HBII-85)

• SNRPN is expressed ubiquitously. In mouse brain, Snord116, Snord115, and Ube3a-antisense are expressed only in neurons. In humans, SNORD116 is expressed at a low level in non-neuronal tissues. Noncoding RNAs at the heart of the PWS locus Which ncRNA is the culprit? Topotecan action on Ube3a imprinting requires the Snord116 PWS locus

Powell et al, PNAS, 2013 Topotecan treatment increases chromatin decondensation of the Snord116 region

Powell et al, PNAS, 2013 Molecular Cell, 2012

DRIP: DNA:RNA immonoprecipitation DRIP-seq:1,972 unique core promoters The mouse Snord116 region gives rise to a G-rich primary RNA and R-loop formation depletes nucleosomes

Powell et al, PNAS, 2013 The endogenous Snord116 region forms R-loops in neurons and topotecan increases R-loop formation at Snord116 DRIP Immuno-FISH Model for topotecan action

Topoisomerase aids transcriptional progression through repetitive region of R-loops and decondensation, but Mouse NPCs topotecan slows this progression and reduces Ube3a-ATS levels Mouse cortex Powell et al, PNAS, 2013 Noncoding RNAs at the heart of the PWS locus Which ncRNA is the culprit? 115HG and 116HG form overlapping, but distinct nuclear RNA clouds that increase in size during neurodevelopment

115HG 116HG Merge Wild-type mouse cortex

RNA Colocalization RNA Cloud Size 100% 2 None p-value <0.01 80% 1.5 60% Incomplete 1 40% 0.5 20% Diameter( µ m) 116HG Complete 0% 115HG 0 E15 E19 P1 P7 P14 P21 P28 P35 P70 E19 P2 P5 Adult

Powell et al, HMG, 2013 Host gene RNA clouds (115HG and 116HG) localize to their own sites of transcription 115HG-RNA/Snrpn-Ube3a-DNA FISH

116HG-RNA/ Snrpn-Ube3a-DNA FISH Host gene RNA cloud 115HG does not colocalize with 116HG encoding DNA

115HG RNA 116HG DNA Merge

116HG RNA 116HG DNA Merge

Chromatin decondensation is responsible for separation of the RNA clouds What are possible functions of 116HG?

Chromatin Isolation by RNA Purification (ChIRP)

Example lncRNA Protein Partners Target Xist, Kcnq1ot1, PRC2/EZH2, HOTTIP! WDR5, RbBP5

Xist, sno-lncRNA! SAF-A, FOX2 Scaffold

Decoy Gas5! Glucocorticoid receptor

Moran et al, Nucleic Acids Research, 2012 116HG interacts with RbBP5

RbBP5 is a member of the MLL1 complex required for H3K4 methylation

Odho 2010, JBC Endogenous interaction In vitro pull-down Control Control Control Control IVT Control 116HG 116HG ! 116HG ! Input oligo oligo Input IVT RNAse A - + - +!

RbBP5 RbBP5

Fox2 Prc2/Ezh2

H3 H3 116HG ChIRP-seq reveals binding sites for 116HG

Powell et al, PNAS, 2013 116HG binds to disnct gene bodies genome-wide

chr4:147,816,642-147,932,984 chr9:110,545,398-110,622,252

Mtor! Nbeal2! Ccdc12!

116HG peaks! 116HG peaks! Control peaks Control peaks

RNA-DNA FISH confirms ChIRP peaks

80 70 60 50 40 30 20 overlapping116HG %cells with 1allele 10 0 Mtor! 116HG! Combined

Powell et al, 2013, in press 116HG binds to genes expressed in brain and involved metabolic pathways

DAVID GO analysis of ChIRP genes

ChIRP peaks identify 2,403 Bonferroni p-value (-log10) genes with interactions Biological Process! mostly distal to promoter 0.00 2.00 4.00 6.00 8.0010.0012.00 cellular protein metabolic protein transport protein modification modification-dependent protein catabolic process cellular protein catabolic process chromatin modification

Tissue Expression! 0.00 5.00 10.0015.0020.0025.0030.0035.0040.0045.00 Brain Brain cortex Hippocampus Liver Bone marrow Cerebellum

Powell et al, 2013, in press Global upregulaon of genes in cortex of 116HG deleon mice

RNA-seq of dissected cortex from adult mice qPCR confirms upregulaon of 3 WT mice tested genes 2 Snord116del mice

6467 genes significantly changed WT vs. Snord116del ! 94% genes upregulated in Snord116del mouse cortex 1201 genes overlapped ChIRP Powell et al, 2013, in press 116HG deleon mice show acvaon of mTOR signaling in the cortex

mTOR immunofluorescence on cortex Phospho-S6 posive cells WT Snord116delsnorddel116 50 45 40 35 WT Snord116del 30 25

Phospho-S6 immunofluorescence on cortex %Positive ! 20 15 10 5 0

WT Snord116del Powell et al, 2013, in press The 116HG lncRNA cloud is larger during sleep cycle and Snord116del mice exhibit diurnal gene dysregulation

Powell et al, 2013, in press Snord116del mice are leaner than WT littermates and have increased lipid oxidation during light hours

CLAMS metabolic chamber

Powell et al, 2013, in press Epigenetics and metabolism of diurnal rhythms

early postnatal life sets up pattern of diurnal metabolism Sleep Feeding Metabolic cycles of catabolism/anabolism

116

Brown R E et al. Physiol Rev 2012;92:1087-1187 Acknowledgements

LaSalle Lab UCD MBP core Collaborators Dag Yasui Mari Golub Frederic Chedin, UC Davis CBS Mike Gonzales Trina Knos Robert Ach, Agilent Diane Schroeder Sean Adams Alice Yamada, Agilent Rima Woods Jon Ramsey Peter Tsang, Agilent Weston Powell Shin-ichi Horike, Kanazawa, Japan Karen Leung Financial Support Makiko Megumo-Horike, Japan Haley Scoles NICHD, NINDS Carolyn Schanen, Nemours, UDE Sarrita Adams Prader-Willli Jim Resnick, University of Florida Keith Dunaway Foundaon Amanda DuBose, UFL Rochelle Coulson Larry Reiter, U of Tennessee Florence Crary Marc Lalande, U Conn Jusn Aflatooni UC Davis Genome Center UC Davis M.I.N.D. Institute