Pulupa Joan M, McArthur Natalie G, Stathi Olga, Wang Miao, Zazhytska Marianna, Pirozzolo Isabella D, Nayar Ahana, Shapiro Lawrence, Lomvardas Stavros
Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA.
Res Sq. 2024 Dec 5:rs.3.rs-5448201. doi: 10.21203/rs.3.rs-5448201/v1.
Ultra long-range genomic contacts, which emerge as prominent components of genome architecture, constitute a biochemical paradox. This is because regulatory DNA elements make selective and stable contacts with DNA sequences located megabases away, instead of interacting with proximal sequences occupied by the same exact transcription factors (TF). This is exemplified in olfactory sensory neurons (OSNs), where only a fraction of Lhx2/Ebf1/Ldb1-bound sites interact with each other, converging into highly selective multi-chromosomal enhancer hubs. reconstitution reveals that TF motif variations impose distinct homotypic properties to their resident Lhx2/Ebf1/Ldb1 complexes, enabling formation of nucleoprotein condensates with solid phase characteristics. Live imaging and single molecule tracking of Lhx2/Ebf1 proteins in cultured OSNs confirm that assembly of transcription-competent solid condensates occurs under physiological protein concentrations. Thus, DNA sequence-induced homophilic nucleoprotein interactions provide a generalizable explanation for the stability and specificity of long-range genomic contacts that control cellular identity and function.
超长距离基因组接触作为基因组结构的重要组成部分出现，构成了一个生化悖论。这是因为调控性DNA元件与位于数百万碱基之外的DNA序列形成选择性和稳定的接触，而不是与由相同转录因子（TF）占据的近端序列相互作用。嗅觉感觉神经元（OSN）就是一个例子，其中只有一小部分Lhx2/Ebf1/Ldb1结合位点相互作用，汇聚成高度选择性的多染色体增强子枢纽。重组实验表明，TF基序变异赋予其所在的Lhx2/Ebf1/Ldb1复合物不同的同型特性，从而能够形成具有固相特征的核蛋白凝聚物。对培养的OSN中Lhx2/Ebf1蛋白进行实时成像和单分子追踪证实，具有转录活性的固体凝聚物在生理蛋白浓度下发生组装。因此，DNA序列诱导的嗜同性核蛋白相互作用为控制细胞特性和功能的长距离基因组接触的稳定性和特异性提供了一个通用的解释。
