Low abundance noncoding antisense RNAs are transcribed from the opposite strand of many genomic loci. These endogenous regulatory elements are shown to regulate corresponding mRNA expression, in some cases through the recruitment of epigenetic enzymes that induce locus-specific chromatin modifications. Inhibition or removal of this subset of antisense transcripts leads to locus-specific up-regulation of sense mRNA and functional protein. We found that brain-derived neurotrophic factor (BDNF) is under the regulatory control of antisense RNAs that transcriptionally suppress the expression of sense mRNA and protein. The main goal of this proposal is to study the role of noncoding RNAs as epigenetic modulators of BDNF expression. Initially, we will study the mechanism of antisense RNA-mediated regulation of BDNF, in vitro, in primary cultures of human and mouse neuroepithelial cells. We will then develop tools to quantitatively measure the interaction between BDNF antisense RNA (BDNF- AS) and the epigenetic enzyme EZH2 to investigate the structural and/or sequence requirements of this interaction. Lastly, we will examine the in vivo effects of Bdnf-AS knockdown on the Bdnf locus, utilizing a mouse model of Rett syndrome (Mecp2 null mice). Studies planned under this proposal will shed light on the molecular mechanisms by which noncoding antisense RNAs, in particular BDNF-AS, regulate expression at the BDNF locus. Our unique approach will lead to identification of the molecular underpinning of noncoding RNA- protein interactions. Finally, we will study the in vivo regulatory role of endogenous BDNF-AS in a mouse model of Rett syndrome. Overall these projects will pave the road for future epigenetic studies on other genomic loci, serving to establish novel noncoding RNA therapeutic targets for several neuropsychological disorders.
We found that brain-derived neurotrophic factor (BDNF) is under the regulatory control of antisense RNAs that suppress the expression of sense mRNA and protein. This project is to investigate the role of noncoding RNAs as epigenetic modulators of BDNF expression. This study will elucidate the molecular mechanisms underpinning antisense RNA-induced chromatin modifications.
|Maghami, Fatemeh; Tabei, Seyed Mohammad Bagher; Moravej, Hossein et al. (2018) Splicing defect in FKBP10 gene causes autosomal recessive osteogenesis imperfecta disease: a case report. BMC Med Genet 19:86|
|Esmaeilzadeh, Hossein; Bordbar, Mohammad Reza; Dastsooz, Hassan et al. (2018) A novel splice site mutation in WAS gene in patient with Wiskott-Aldrich syndrome and chronic colitis: a case report. BMC Med Genet 19:123|
|Dastsooz, Hassan; Nemati, Hamid; Fard, Mohammad Ali Farazi et al. (2017) Novel mutations in PANK2 and PLA2G6 genes in patients with neurodegenerative disorders: two case reports. BMC Med Genet 18:87|
|Bordbar, Mohammad Reza; Modarresi, Farzaneh; Farazi Fard, Mohammad Ali et al. (2017) A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis. BMC Med Genet 18:49|
|Karimzadeh, Parvaneh; Naderi, Samaneh; Modarresi, Farzaneh et al. (2017) Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene. BMC Med Genet 18:73|
|Khorkova, Olga; Wahlestedt, Claes (2017) Oligonucleotide therapies for disorders of the nervous system. Nat Biotechnol 35:249-263|
|Velmeshev, Dmitry; Lally, Patrick; Magistri, Marco et al. (2016) CANEapp: a user-friendly application for automated next generation transcriptomic data analysis. BMC Genomics 17:49|
|Magistri, Marco; Khoury, Nathalie; Mazza, Emilia Maria Cristina et al. (2016) A comparative transcriptomic analysis of astrocytes differentiation from human neural progenitor cells. Eur J Neurosci 44:2858-2870|
|Magistri, Marco; Velmeshev, Dmitry; Makhmutova, Madina et al. (2016) The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer's Disease. Curr Alzheimer Res 13:985-95|
|Yamanaka, Yasunari; Faghihi, Mohammad Ali; Magistri, Marco et al. (2015) Antisense RNA controls LRP1 Sense transcript expression through interaction with a chromatin-associated protein, HMGB2. Cell Rep 11:967-976|
Showing the most recent 10 out of 15 publications