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.

有人提议HOTAIR来调节反式中的HoxD簇基因或顺式中的HoxC簇基因，这一机制尚不清楚。我们已经确定了32个核苷酸的保守非编码元件（CNE）作为HOTAIR古代序列，很可能起源于脊椎动物的根。第二轮全基因组复制在HOTAIR中产生了一个CNE副本，在HOXD11的非编码转录本中嵌入了另一个副本。同源的CNE经历了补偿性突变，相对于转录本的方向性表现出序列互补性，并且在体外具有很高的亲和力。该HOTAIRCNE在干细胞中类似于稳定的增强子，在表达HOTAIR的细胞中类似于活性增强子。HOTAIR表达与HOXC11在顺式中正相关，与HOXD11在反式中负相关。我们提出了一种HOTAIR调节的双重形式，其中HOTAIR及其嵌入的增强子的转录调节顺式HOXC11，同源的CNE之间的序列互补性暗示了HOXD11的反式调节。