The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2

Author:

Han Xue1,Zhang Jiejie2,Liu Yaxi2,Fan Xiaoying3,Ai Shanshan2,Luo Yingjie2,Li Xin2,Jin Hengwei4,Luo Sai1,Zheng Hui1ORCID,Yue Yanzhu2,Chang Zai1,Yang Zhongzhou4,Tang Fuchou3,He Aibin2ORCID,Shen Xiaohua1ORCID

Affiliation:

1. Tsinghua Center for Life Sciences, School of Medicine, and School of Life Sciences, Tsinghua University, Beijing 100084, China

2. Peking Center for Life Sciences, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China

3. Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Peking University, Beijing 100871, China

4. Model Animal Research Center, Nanjing University, Nanjing 210061, China

Abstract

ABSTRACT 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 Hand2os1/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 Hand2os1 transcription to ∼8-32%, but fails to affect HAND2 expression and yields no discernable heart phenotypes. Interestingly, full-length deletion of Hand2os1 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 Hand2os1 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 Hand2os1 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.

Funder

National Basic Research Program of China

National Natural Science Foundation of China

Center for Life Sciences (CLS) at Tsinghua University

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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