Nepal Chirag, Taranta Andrzej, Hadzhiev Yavor, Pundhir Sachin, Mydel Piotr, Lenhard Boris, Müller Ferenc, Andersen Jesper B
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
iScience. 2020 Apr 24;23(4):101008. doi: 10.1016/j.isci.2020.101008. Epub 2020 Mar 25.
HOTAIR was proposed to regulate either HoxD cluster genes in trans or HoxC cluster genes in cis, a mechanism that remains unclear. We have identified a 32-nucleotide conserved noncoding element (CNE) as HOTAIR ancient sequence that likely originated at the root of vertebrate. The second round of whole-genome duplication resulted in one copy of the CNE within HOTAIR and another copy embedded in noncoding transcript of HOXD11. Paralogous CNEs underwent compensatory mutations, exhibit sequence complementarity with respect to transcripts directionality, and have high affinity in vitro. The HOTAIR CNE resembled a poised enhancer in stem cells and an active enhancer in HOTAIR-expressing cells. HOTAIR expression is positively correlated with HOXC11 in cis and negatively correlated with HOXD11 in trans. We propose a dual modality of HOTAIR regulation where transcription of HOTAIR and its embedded enhancer regulates HOXC11 in cis and sequence complementarity between paralogous CNEs suggests HOXD11 regulation in trans.
HOTAIR被认为可通过反式作用调控HoxD基因簇中的基因，或通过顺式作用调控HoxC基因簇中的基因，但其机制仍不清楚。我们已鉴定出一个32个核苷酸的保守非编码元件（CNE）作为HOTAIR的古老序列，它可能起源于脊椎动物的起源时期。第二轮全基因组复制导致该CNE的一个拷贝存在于HOTAIR中，另一个拷贝嵌入到HOXD11的非编码转录本中。旁系同源CNE发生了补偿性突变，在转录本方向性方面表现出序列互补性，并且在体外具有高亲和力。HOTAIR CNE在干细胞中类似于一个就绪增强子，在表达HOTAIR的细胞中则类似于一个活性增强子。HOTAIR的表达在顺式作用中与HOXC11呈正相关，在反式作用中与HOXD11呈负相关。我们提出了一种HOTAIR调控的双重模式，即HOTAIR及其嵌入的增强子的转录在顺式作用中调控HOXC11，旁系同源CNE之间的序列互补性表明在反式作用中调控HOXD11。
