Active chromatin marks drive spatial sequestration of heterochromatin in C. elegans nuclei
Active chromatin marks drive spatial sequestration of heterochromatin in C. elegans nuclei
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DOI：
10.1038/s41586-019-1243-y
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发表时间：
2019-05-30
期刊：
影响因子：
64.8
通讯作者：
Gasser, Susan M.
中科院分区：
文献类型：
--
作者：
Cabianca, Daphne S.;Munoz-Jimenez, Celia;Gasser, Susan M.
基因表达的发育程序的执行需要将基因组准确地划分为亚核区室，其中活性常染色质集中富集，而沉默异染色质位于核周边（1）。与核纤层蛋白A突变相关的退行性疾病的存在表明染色质的核周结合有助于细胞类型的完整性（2，3）。组蛋白H3（H3 K9 me）赖氨酸9的甲基化表征异染色质，并介导转录抑制和染色质锚定在内核膜上（4）。在秀丽隐杆线虫胚胎中，染色质结构域蛋白CEC-4通过H3 K9 me与内核膜系链异染色质结合（3，5），而在分化的组织中，诱导了第二个异染色质螯合途径。在这里，我们使用的cec-4背景的RNA干扰屏幕和确定MRG-1作为一个广泛表达的因素，这是必要的第二个染色质锚在肠细胞。然而，MRG-1仅与常染色质结合，表明它间接起作用。双mrg-1; cec-4突变体中的异染色质脱离通过耗尽组蛋白乙酰转移酶CBP-1/p300或转录因子ATF-8（bZIP家族的成员（已知其募集CBP/p300））来拯救。cec-4突变体中CBP-1的过表达足以以ATF-8依赖性方式使异染色质离域。CBP-1和H3 K27 ac水平在mrg-1敲低后异染色质中增加，与离域一致。这表明C. elegans是由沉默染色质的直接核周附着和CBP-1/p300在常染色质中的主动保留来调节的。这两种途径在胚胎和幼虫组织中的作用不同，CBP-1被MRG-1隔离在分化细胞中起主要作用。
The execution of developmental programs of gene expression requires an accurate partitioning of the genome into subnuclear compartments, with active euchromatin enriched centrally and silent heterochromatin at the nuclear periphery(1). The existence of degenerative diseases linked to lamin A mutations suggests that perinuclear binding of chromatin contributes to cell-type integrity(2,3). The methylation of lysine 9 of histone H3 (H3K9me) characterizes heterochromatin and mediates both transcriptional repression and chromatin anchoring at the inner nuclear membrane(4). In Caenorhabditis elegans embryos, chromodomain protein CEC-4 bound to the inner nuclear membrane tethers heterochromatin through H3K9me(3,5), whereas in differentiated tissues, a second heterochromatin-sequestering pathway is induced. Here we use an RNA interference screen in the cec-4 background and identify MRG-1 as a broadly expressed factor that is necessary for this second chromatin anchor in intestinal cells. However, MRG-1 is exclusively bound to euchromatin, suggesting that it acts indirectly. Heterochromatin detachment in double mrg-1; cec-4 mutants is rescued by depleting the histone acetyltransferase CBP-1/p300 or the transcription factor ATF-8, a member of the bZIP family (which is known to recruit CBP/p300). Overexpression of CBP-1 in cec-4 mutants is sufficient to delocalize heterochromatin in an ATF-8-dependent manner. CBP-1 and H3K27ac levels increase in heterochromatin upon mrg-1 knockdown, coincident with delocalization. This suggests that the spatial organization of chromatin in C. elegans is regulated both by the direct perinuclear attachment of silent chromatin, and by an active retention of CBP-1/p300 in euchromatin. The two pathways contribute differentially in embryos and larval tissues, with CBP-1 sequestration by MRG-1 having a major role in differentiated cells.