Malat1 as an evolutionarily conserved lncRNA, plays a positive role in regulating proliferation and maintaining undifferentiated status of early-stage hematopoietic cells.
BACKGROUND
The metastasis-associated lung adenocarcinoma transcription 1 (Malat1) is a highly conserved long non-coding RNA (lncRNA) gene. Previous studies showed that Malat1 is abundantly expressed in many tissues and involves in promoting tumor growth and metastasis by modulating gene expression and target protein activities. However, little is known about the biological function and regulation mechanism of Malat1 in normal cell proliferation.


RESULTS
In this study we conformed that Malat1 is highly conserved across vast evolutionary distances amongst 20 species of mammals in terms of sequence, and found that mouse Malat1 expresses in tissues of liver, kidney, lung, heart, testis, spleen and brain, but not in skeletal muscle. After treating erythroid myeloid lymphoid (EML) cells with All-trans Retinoic Acid (ATRA), we investigated the expression and regulation of Malat1 during hematopoietic differentiation, the results showed that ATRA significantly down regulates Malat1 expression during the differentiation of EML cells. Mouse LRH (Lin-Rhodamine(low) Hoechst(low)) cells that represent the early-stage progenitor cells show a high level of Malat1 expression, while LRB (Lin - Hoechst(Low) Rhodamine(Bright)) cells that represent the late-stage progenitor cells had no detectable expression of Malat1. Knockdown experiment showed that depletion of Malat1 inhibits the EML cell proliferation. Along with the down regulation of Malat1, the tumor suppressor gene p53 was up regulated during the differentiation. Interestingly, we found two p53 binding motifs with help of bioinformatic tools, and the following chromatin immunoprecipitation (ChIP) test conformed that p53 acts as a transcription repressor that binds to Malat1's promoter. Furthermore, we testified that p53 over expression in EML cells causes down regulation of Malat1.


CONCLUSIONS
In summary, this study indicates Malat1 plays a critical role in maintaining the proliferation potential of early-stage hematopoietic cells. In addition to its biological function, the study also uncovers the regulation pattern of Malat1 expression mediated by p53 in hematopoietic differentiation. Our research shed a light on exploring the Malat1 biological role including therapeutic significance to inhibit the proliferation potential of malignant cells.
Department of Pathology, Yale University School of Medicine, New Haven, USA. xian-yong.ma@yale.edu.
Xian-Yong
XY
Ma
Department of Pathology, Yale University School of Medicine, New Haven, USA. jianhui.wang@yale.edu.
Jian-Hui
JH
Wang
Department of Pathology, Yale University School of Medicine, New Haven, USA. jinglan.wang@yale.edu.
Jing-Lan
JL
Wang
University of Connecticut School of Medicine, Farmington, USA. xiaodong88ma@gmail.com.
Charles X
CX
Ma
Department of Surgical Oncology, Affiliated Hospital of Hebei University, Baoding, China. xiaochun.wang@yale.edu.
Xiao-Chun
XC
Wang
College of Life Sciences, Hebei University, Baoding, China. liufengsong@hbu.edu.cn.
Feng-Song
FS
Liu
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D017124:Conserved Sequence / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D019143:Evolution, Molecular; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D011323:Primates; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C557041:MALAT1 long non-coding RNA, human; C557040:Malat1 long non-coding RNA, mouse; D062085:RNA, Long Noncoding; D016159:Tumor Suppressor Protein p53; D014212:Tretinoin