RNA constitutes a large fraction of chromatin. Spatial distribution and functional relevance of most of RNA-chromatin interactions remain unknown. We established a landscape analysis of RNA-chromatin interactions in human acute myeloid leukemia (AML). In total more than 50 million interactions were captured in an AML cell line. Protein-coding mRNAs and long non-coding RNAs exhibited a substantial number of interactions with chromatin in cis suggesting transcriptional activity. In contrast, small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) associated with chromatin predominantly in trans suggesting chromatin specific functions. Of note, snoRNA-chromatin interaction was associated with chromatin modifications and occurred independently of the classical snoRNA-RNP complex. Two C/D box snoRNAs, namely SNORD118 and SNORD3A, displayed high frequency of trans-association with chromatin. The transcription of SNORD118 and SNORD3A was increased upon leukemia transformation and enriched in leukemia stem cells, but decreased during myeloid differentiation. Suppression of SNORD118 and SNORD3A impaired leukemia cell proliferation and colony forming capacity in AML cell lines and primary patient samples. Notably, this effect was leukemia specific with less impact on healthy CD34+ hematopoietic stem and progenitor cells. These findings highlight the functional importance of chromatin-associated RNAs overall and in particular of SNORD118 and SNORD3A in maintaining leukemia propagation.

RNA 构成染色质的很大一部分。大多数 RNA-染色质相互作用的空间分布和功能相关性仍然未知。我们建立了人类急性髓系白血病 (AML) 中 RNA-染色质相互作用的景观分析。在 AML 细胞系中总共捕获了超过 5000 万次相互作用。蛋白质编码 mRNA 和长非编码 RNA 表现出大量与顺式染色质的相互作用，表明具有转录活性。相比之下，与染色质相关的小核仁 RNA (snoRNA) 和小核 RNA (snRNA) 主要呈反式，表明染色质具有特定功能。值得注意的是，snoRNA-染色质相互作用与染色质修饰相关，并且独立于经典的 snoRNA-RNP 复合物发生。两种 C/D 盒 snoRNA，即 SNORD118 和 SNORD3A，显示出与染色质的高频率反式关联。 SNORD118和SNORD3A的转录在白血病转化时增加并在白血病干细胞中富集，但在骨髓分化期间减少。抑制 SNORD118 和 SNORD3A 会损害 AML 细胞系和原发性患者样本中的白血病细胞增殖和集落形成能力。值得注意的是，这种效应是白血病特异性的，对健康 CD34+ 造血干细胞和祖细胞的影响较小。这些发现强调了染色质相关 RNA 的整体功能重要性，特别是 SNORD118 和 SNORD3A 在维持白血病增殖中的功能重要性。