期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：37
DOI：10.1073/pnas.2211642119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Diverse regulatory mechanisms balance X-chromosome gene expression between sexes in mammals, fruit flies, and nematodes (XY/XO males and XX females/hermaphrodites). We identify DNA motifs on X that recruit dosage compensation complexes (DCCs) in nematode hermaphrodites to reduce X-chromosome expression. Recruitment sites on X, but not regions on autosomes, contain diverse combinations of different motifs or multiple copies of one motif. DCC binding studies in vivo and in vitro of wild-type and mutant X-recruitment sites validate motif usage. We find that clustering of motifs in different combinations with appropriate orientation and spacing promotes synergy in DCC binding, thereby triggering DCC assembly specifically along X. We demonstrate how regulatory complexes can be recruited across an entire chromosome to control its gene expression.
Organisms that count X-chromosome number to determine sex utilize dosage compensation mechanisms to balance X-gene expression between sexes. Typically, a regulatory complex is recruited to X chromosomes of one sex to modulate gene expression. A major challenge is to determine the mechanisms that target regulatory complexes specifically to X. Here, we identify critical X-sequence motifs in
Caenorhabditis elegans that act synergistically in hermaphrodites to direct X-specific recruitment of the dosage compensation complex (DCC), a condensin complex. We find two DNA motifs that collaborate with a previously defined 12-bp motif called MEX (motif enriched on X) to mediate binding: MEX II, a 26-bp X-enriched motif and Motif C, a 9-bp motif that lacks X enrichment. Inserting both MEX and MEX II into a new location on X creates a DCC binding site equivalent to an endogenous recruitment site, but inserting only MEX or MEX II alone does not. Moreover, mutating MEX, MEX II, or Motif C in endogenous recruitment sites with multiple different motifs dramatically reduces DCC binding in vivo to nearly the same extent as mutating all motifs. Changing the orientation or spacing of motifs also reduces DCC binding. Hence, synergy in DCC binding via combinatorial clustering of motifs triggers DCC assembly specifically on X chromosomes. Using an in vitro DNA binding assay, we refine the features of motifs and flanking sequences that are critical for DCC binding. Our work reveals general principles by which regulatory complexes can be recruited across an entire chromosome to control its gene expression.
