Phase separation drives aberrant chromatin looping and cancer development.
Phase separation drives aberrant chromatin looping and cancer development.
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相位分离驱动异常的染色质循环和癌症发展。
DOI：
10.1038/s41586-021-03662-5
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发表时间：
2021-07
期刊：
影响因子：
64.8
通讯作者：
Wang GG
中科院分区：
文献类型：
--
作者：
Ahn JH;Davis ES;Daugird TA;Zhao S;Quiroga IY;Uryu H;Li J;Storey AJ;Tsai YH;Keeley DP;Mackintosh SG;Edmondson RD;Byrum SD;Cai L;Tackett AJ;Zheng D;Legant WR;Phanstiel DH;Wang GG
癌症的发展与靶向具有内在无序区域（IDR）的蛋白质的遗传异常密切相关。在人类血液恶性肿瘤中，核孔蛋白（NUP 98或NUP 214）的复发性染色体易位产生异常嵌合体，其总是保留核孔蛋白的IDR，串联分散的苯丙氨酸和甘氨酸（FG）重复序列。然而，它仍然是难以捉摸的非结构化的IDR如何有助于肿瘤发生。我们表明，IDR窝藏在NUP 98-HOXA 9，含有同源结构域的转录因子（TF）嵌合体中反复检测白血病，是必不可少的建立液-液相分离（LLPS）斑点的嵌合体和诱导白血病转化。值得注意的是，NUP 98-HOXA 9的LLPS不仅促进嵌合体TF的染色质占据，而且还需要形成广泛的“超级增强子”样结合模式，通常在一系列致白血病基因中可见，从而增强其转录激活。通过将NUP 98的FG重复序列替换为FUS的不相关LLPS形成IDR而产生的人工HOX嵌合体对嵌合体的全基因组结合和靶基因激活具有类似的增强作用。染色体构象捕获技术如Hi-C作图进一步证明了相分离的NUP 98-H 0XA 9诱导在原癌基因处富集的CTCF非依赖性染色质成环。总之，这份报告描述了一个原理证明的例子，其中癌症获得突变，以建立致癌TF凝聚物通过相分离，这同时增强了他们的基因组靶向，并诱导组织异常的三维染色质结构在肿瘤转化。由于LLPS感受态分子经常与疾病有关，因此这种机制可能被推广到许多恶性和病理性环境。
The development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains the nucleoporin’s IDR, tandemly dispersed phenylalanine-and-glycine (FG) repeats. However, it remains elusive how unstructured IDRs contribute to oncogenesis. We show that IDR harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in leukemias, is essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukemic transformation. Notably, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TFs but is also required for formation of a broad, ‘super-enhancer’-like binding pattern, typically seen at a battery of leukemogenic genes, potentiating their transcriptional activation. An artificial HOX chimera, created by replacing NUP98’s FG repeats with an unrelated LLPS-forming IDR of FUS, had similar enhancement effects on chimera’s genome-wide binding and target gene activation. Chromosome conformation capture techniques such as Hi-C mapping further demonstrated that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin looping enriched at proto-oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish oncogenic TF condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As LLPS-competent molecules are frequently implicated in diseases, this mechanism can potentially be generalized to many malignant and pathological settings.