Wong Emily S, Schmitt Bianca M, Kazachenka Anastasiya, Thybert David, Redmond Aisling, Connor Frances, Rayner Tim F, Feig Christine, Ferguson-Smith Anne C, Marioni John C, Odom Duncan T, Flicek Paul
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
University of Cambridge, Cancer Research UK-Cambridge Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK.
Nat Commun. 2017 Oct 23;8(1):1092. doi: 10.1038/s41467-017-01037-x.
Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis-acting variants generally exhibit additive inheritance, while those linked to trans-acting variants are most often dominantly inherited. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states.
非编码调控变异在人类疾病遗传学和进化中起着核心作用。在此，我们测量了两种近交系小鼠品系杂交后代中三种肝脏特异性转录因子的等位基因特异性转录因子结合占有率，以阐明哺乳动物中转录因子结合变异背后的调控机制。我们的结果突出了顺式作用变异在转录因子占有率差异方面的首要地位。与顺式作用变异相关的转录因子结合差异通常表现为加性遗传，而与反式作用变异相关的差异则大多为显性遗传。顺式作用变异导致转录因子占有率的局部协调，这种协调随距离衰减；同时也观察到了远端协调，其可能受长程染色质接触的调节。我们的结果揭示了在复杂的哺乳动物细胞状态下相互作用以驱动转录因子占有率、染色质状态和基因表达的调控机制。
