Naturally-ocurring genetic variation between individuals affects promoter strength and shape through distinct mechanisms

SCHOR IE*; DEGNER JF*; CANNAVÒ E; SHIM H; CASALE FP; BIRNEY E; STEGLE O; FURLONG EE

Heidelberg

Conferencia; 11th EMBL Conference: ?Transcription and Chromatin?; 2014

EMBL

<!-- /* Font Definitions */@font-face{font-family:"ＭＳ 明朝";mso-font-charset:78;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1791491579 18 0 131231 0;}@font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Cambria;panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;mso-pagination:widow-orphan;font-size:12.0pt;font-family:Cambria;mso-ascii-font-family:Cambria;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Cambria;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-family:Cambria;mso-ascii-font-family:Cambria;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Cambria;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;}@page WordSection1{size:612.0pt 792.0pt;margin:72.0pt 90.0pt 72.0pt 90.0pt;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}-->Transcription initiation is controlled bythe activity of promoter proximal and distal cis-regulatory elements, which ultimately modulate RNA pol IIactivity at transcriptional start sites (TSS). While the location and shape ofTSS clusters have been described at a genome-wide level, the features that definethe position, number and usage of TSSs remain unknown, and yet are essential tounderstand complex trait genetics and gene-regulatory evolution.Here, we performed a comprehensive study ofpopulation variation in TSSs during embryonic development using Cap-Analysis ofGene Expression (CAGE) and quantitative trait locus (QTL) mapping across a collectionof Drosophila melanogaster inbred wild-isolates.In a developmental time course, we identified thousands of QTLs, within whichtime-independent effects have prevalence. Using associations against principal-componentdata decompositions, we detect a range of transcriptional start sites QTL(tssQTL) types. These include classes that are generally missed using common eQTLapproaches, such as effects on the shape of TSS clusters, the usage andposition of specific TSSs within a cluster and the relative strand activity inbi-directional promoters.Surprisingly, tssQTLs separate into two distinctgroups: QTLs with a directional effect on promoter output and QTLs where spatialredistribution of initiation results in promoter shape changes, with minimal effecton overall RNA levels. The polymorphisms leading to directional vs.redistribution QTLs differ in their motif enrichment and proximity to thepromoters, with redistribution QTLs being preferentially located in corepromoter regions and affecting binding sites for proteins known to interactwith basal transcription machinery.These specific features associated with eachclass support their distinction into mechanistically different tssQTLs, whileproviding novel insights for understanding the details of transcriptional initiationand the evolution of promoter function.