Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα).
De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous null males are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERα-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERα-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in the metabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaic males. Overall we define and characterize a novel mechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERα-dependent. This PCDH19-NONO-ERα axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERα and generally nuclear hormone receptor-associated cancers.
Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia.|Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia.
Duyen H
DH
Pham
Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia.
Chuan C
CC
Tan
School of Biological Sciences, The University of Adelaide, Adelaide 5000, Australia.
Claire C
CC
Homan
Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia.|Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia.
Kristy L
KL
Kolc
Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia.|Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia.
Mark A
MA
Corbett
School of Biological Sciences, The University of Adelaide, Adelaide 5000, Australia.
Dale
D
McAninch
School of Human Sciences and School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009 and Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, 6009, Australia.
Archa H
AH
Fox
School of Biological Sciences, The University of Adelaide, Adelaide 5000, Australia.
Paul Q
PQ
Thomas
Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia.|Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia.
Raman
R
Kumar
Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia.|Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia.|School of Biological Sciences, The University of Adelaide, Adelaide 5000, Australia.|South Australian Health and Medical Research Institute, Adelaide 5000, Australia.
Jozef
J
Gecz
D001943:Breast Neoplasms / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004827:Epilepsy / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D009154:Mutation; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D050810:Octamer Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D000091363:Protocadherins; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; C083214:NONO protein, human; D034521:Nuclear Matrix-Associated Proteins; D050810:Octamer Transcription Factors; C438605:PCDH19 protein, human; D000091363:Protocadherins; D016601:RNA-Binding Proteins