Two novel DXZ4-associated long noncoding RNAs show developmental changes in expression coincident with heterochromatin formation at the human (Homo sapiens) macrosatellite repeat.
Two novel DXZ4-associated long noncoding RNAs show developmental changes in expression coincident with heterochromatin formation at the human (Homo sapiens) macrosatellite repeat.
复制标题
DOI：
10.1007/s10577-015-9479-3
复制
发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Chadwick BP
中科院分区：
文献类型：
--
作者：
Figueroa DM;Darrow EM;Chadwick BP
在男性X和女性活动X染色体（Xa）上，大卫星重复（MSR）DXZ 4被包装成以CpG甲基化和组蛋白H3在赖氨酸-9（H3 K9 me 3）处三甲基化为特征的组成型异染色质。相反，女性非活性X染色体（Xi）上的DXZ 4被包装到常染色质中，被建筑蛋白CCCTC结合因子结合，并介导Xi特异性长距离顺式接触，与Xi上类似包装的串联重复序列。在癌症中，男性DXZ 4可以不适当地恢复到Xi样状态，并且据报道其他MSR响应于疾病而采用替代的染色质构型。鉴于这种可塑性，我们试图确定可能控制DXZ 4异染色质的因素。在人类胚胎干细胞中，我们发现DXZ 4处的5-羟甲基胞嘧啶水平较低，并且随着H3 K9 me 3的获得，该标记在分化时丢失。我们确定了两个以前未描述的DXZ 4相关的非编码转录本（DANT 1和DANT 2），它们从阵列侧翼的启动子转录到DXZ 4。每一种都产生穿过MSR的转录物同种型。然而，在分化时，Zeste-2的增强子使DANT 1沉默，并且DANT 2转录在进入DXZ 4之前终止。这些数据支持一个模型，其中DANT 1和/或DANT 2可以发挥作用，以调节在该MSR的组成型异染色质形成。
On the male X and female active X chromosome (Xa), the macrosatellite repeat (MSR) DXZ4 is packaged into constitutive heterochromatin characterized by CpG methylation and histone H3 tri-methylated at lysine-9 (H3K9me3). In contrast, DXZ4 on the female inactive X chromosome (Xi), is packaged into euchromatin, is bound by the architectural protein CCCTC-binding factor, and mediates Xi-specific long-range cis contact with similarly packaged tandem repeats on the Xi. In cancer, male DXZ4 can inappropriately revert to a Xi-like state and other MSRs have been reported to adopt alternate chromatin configurations in response to disease. Given this plasticity, we sought to identify factors that might control heterochromatin at DXZ4. In human embryonic stem cells, we found low levels of 5-hydroxymethylcytosine at DXZ4, and that this mark is lost upon differentiation as H3K9me3 is acquired. We identified two previously undescribed DXZ4 associated non-coding transcripts (DANT1 and DANT2) that are transcribed towards DXZ4 from promoters flanking the array. Each generates transcript isoforms that traverse the MSR. However, upon differentiation, Enhancer of Zeste-2 silences DANT1, and DANT2 transcription terminates prior to entering DXZ4. These data support a model wherein DANT1 and/or DANT2 may function to regulate constitutive heterochromatin formation at this MSR.