The ISW1a ATP-dependent chromatin remodeler acts specifically on dinucleosomes to regulate early transcription [MNase-Seq]

The large family of ATP-dependent chromatin remodelers that regulate chromatin organization and composition are thought to act only on individual mononucleosomes. We discovered however that the yeast ISW1a remodeler has a much higher affinity for dinucleosomes and only efficiently converts ATP hydrolysis into nucleosome movement when bound to dinucleosomes, not mononucleosomes. The Ioc3 accessory subunit and its HLB DNA binding domain confer dinucleosome specificity onto the Isw1 catalytic subunit. Perturbation of ISW1a dinucleosome specificity by mutating Ioc3 interferes with its localization immediately downstream of the early transcription complex. ISW1a and NuA4, a histone acetyl transferase, and SWR1, a histone exchanger, are required together to slow early passage of RNA polymerase II. These findings provide new insights into the unusual specificity of a chromatin remodeler regulating the transition from transcription initiation to elongation and its functional interplay with other chromatin modifiers.调控染色质组织与组成的庞大ATP依赖型染色质重塑因子（ATP-dependent chromatin remodelers）家族，此前被认为仅能作用于单个单核小体（mononucleosome）。然而我们的研究发现，酵母ISW1a染色质重塑因子对双核小体（dinucleosomes）具有更高的亲和力，且仅在结合双核小体时，才能高效将ATP水解转化为核小体移位，而非单核小体。Ioc3辅助亚基及其HLB DNA结合结构域，可赋予Isw1催化亚基双核小体识别特异性。通过突变Ioc3扰乱ISW1a的双核小体识别特异性，会干扰其在早期转录复合物下游紧邻区域的定位。ISW1a与组蛋白乙酰转移酶（histone acetyl transferase）NuA4、组蛋白交换因子（histone exchanger）SWR1三者协同作用，共同减慢RNA聚合酶II的早期转录进程。本研究结果为染色质重塑因子调控转录起始至延伸的过渡过程中的独特特异性，及其与其他染色质修饰因子的功能互作，提供了全新的认知视角。