期刊
DEVELOPMENT
卷 146, 期 13, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.176198
关键词
lncRNA; Hand2osl; Hand2; Knockout mice; Single cell transcriptomic analysis; Heart development
资金
- National Basic Research Program of China [2018YFA0107604, 2017YFA0504204, 2017YFA0103402]
- National Natural Science Foundation of China [31630095, 31571487, 31771607]
- Center for Life Sciences (CLS) at Tsinghua University
Exploration and dissection of potential actions and effects of long noncoding RNA (lncRNA) in animals remain challenging. Here, using multiple knockout mouse models and single cell RNA sequencing, we demonstrate that the divergent lncRNA Hand2osl/Uph has a key complex modulatory effect on the expression of its neighboring gene HAND2 and subsequently on heart development and function. Short deletion of the Hand2os1 promoter in mouse diminishes Hand2osl transcription to similar to 8-32%, but fails to affect HAND2 expression and yields no discernable heart phenotypes. Interestingly, full-length deletion of Hand2osl in mouse causes moderate yet prevalent upregulation of HAND2 in hundreds of cardiac cells, leading to profound biological consequences, including dysregulated cardiac gene programs, congenital heart defects and perinatal lethality. We propose that the Hand2osl locus dampens HAND2 expression to restrain cardiomyocyte proliferation, thereby orchestrating a balanced development of cardiac cell lineages. This study highlights the regulatory complexity of the lncRNA Hand2osl on HAND2 expression, emphasizing the need for complementary genetic and single cell approaches to delineate the function and primary molecular effects of an lncRNA in animals.
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