We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. However, DNA mutations alone do not fully explain malignant transformation4,5,6,7. Spiteri I, Lynn C, Mossner M, Kimberley C, Fernandez-Mateos J, Chen B, Zapata L, James C, Barozzi I, Chkhaidze K, Nichol D, Gunasri V, Berner A, Schmidt M, Lakatos E, Baker A-M, Costa H, Mitchinson M, Piazza R, Jansen M, Caravagna G, Ramazzotti D, Shibata D, Bridgewater J, Rodriguez-Justo M, Magnani L, Graham TA, Sottoriva A et al., 2022, The co-evolution of the genome and epigenome in colorectal cancer, Nature, Vol: 611, Pages: 733-743, ISSN: 0028-0836Ĭolorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11-80 kb in size) from the genome. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes1-3, but the overall extent to which this occurs remains unknown. ![]() Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. ![]() Hu R, Zhang Y, Li B, Alcaina Caro A, Fukuda-Yuzawa Y, Kelman G, Akeza A, Blow MJ, Pham Q, Harrington AN, Godoy J, Meky EM, von Maydell K, Hunter RD, Akiyama JA, Novak CS, Plajzer-Frick I, Afzal V, Tran S, Lopez-Rios J, Talkowski ME, Lloyd KCK, Ren B, Dickel DE, Visel A, Pennacchio LA et al., 2023, Topologically associating domain boundaries are required for normal genome function, Communications Biology, Vol: 6, ISSN: 2399-3642
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |