Xuedong Kang1, Yan Zhao1, Marlin Touma1,2, Ashley A Cass3, Fuying Gao4, Reshma Biniwale5, Giovanni Coppola4, Xinshu Xiao3, Brian Reemtsen5, Yibin Wang2,6. 1. The Children's Discovery and Innovation Institute (CDI), Department of Pediatrics, University of California, Los Angeles, CA. 2. Cardiovascular Research Laboratory, University of California, Los Angeles, CA. 3. Department of Integrative Biology and Physiology, University of California, Los Angeles, CA. 4. Department of Neurology and Psychiatry, University of California, Los Angeles, CA. 5. Department of Cardiothoracic Surgery, University of California, Los Angeles, CA. 6. Department of Anesthesiology, Physiology and Medicine, University of California, Los Angeles, CA.
Abstract
BACKGROUND: Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated. METHODS AND RESULTS: From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes. CONCLUSIONS: The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects.
BACKGROUND: Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated. METHODS AND RESULTS: From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes. CONCLUSIONS: The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects.
Authors: Phillip Grote; Lars Wittler; David Hendrix; Frederic Koch; Sandra Währisch; Arica Beisaw; Karol Macura; Gaby Bläss; Manolis Kellis; Martin Werber; Bernhard G Herrmann Journal: Dev Cell Date: 2013-01-28 Impact factor: 12.270
Authors: Nicholas J Schurch; Pietá Schofield; Marek Gierliński; Christian Cole; Alexander Sherstnev; Vijender Singh; Nicola Wrobel; Karim Gharbi; Gordon G Simpson; Tom Owen-Hughes; Mark Blaxter; Geoffrey J Barton Journal: RNA Date: 2016-03-28 Impact factor: 4.942
Authors: Yan Zhao; Xuedong Kang; Fuying Gao; Alejandra Guzman; Ryan P Lau; Reshma Biniwale; Madhuri Wadehra; Brian Reemtsen; Meena Garg; Nancy Halnon; Fabiola Quintero-Rivera; Glen Van Arsdell; Giovanni Coppola; Stanley F Nelson; Marlin Touma Journal: J Mol Med (Berl) Date: 2019-12-13 Impact factor: 4.599
Authors: Yan Zhao; Xuedong Kang; Alexander Barsegian; Jian He; Alejandra Guzman; Ryan P Lau; Reshma Biniwale; Madhuri Wadhra; Brian Reemtsen; Meena Garg; Nancy Halnon; Fabiola Quintero-Rivera; Wayne W Grody; Glen Van Arsdell; Stanley F Nelson; Marlin Touma Journal: J Mol Med (Berl) Date: 2020-06-12 Impact factor: 4.599
Authors: Marlin Touma; Brian Reemtsen; Nancy Halnon; Juan Alejos; J Paul Finn; Stanley F Nelson; Yibin Wang Journal: Front Cardiovasc Med Date: 2017-06-01
Authors: Joel L Berry; Wuqiang Zhu; Yao Liang Tang; Prasanna Krishnamurthy; Ying Ge; John P Cooke; Yabing Chen; Daniel J Garry; Huang-Tian Yang; Namakkal Soorapan Rajasekaran; Walter J Koch; Song Li; Keitaro Domae; Gangjian Qin; Ke Cheng; Timothy J Kamp; Lei Ye; Shijun Hu; Brenda M Ogle; Jack M Rogers; E Dale Abel; Michael E Davis; Sumanth D Prabhu; Ronglih Liao; William T Pu; Yibin Wang; Peipei Ping; Nenad Bursac; Gordana Vunjak-Novakovic; Joseph C Wu; Roberto Bolli; Philippe Menasché; Jianyi Zhang Journal: Circ Res Date: 2019-01-04 Impact factor: 17.367