Cargando…

Utilization of NGS technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance

NGS (Next Generation Sequencing) technologies allows us to determine key gene expression signatures that correlate with resistance (and responsiveness) to anti-cancer therapeutics. We have undertaken a transcriptomic and chromatin immunoprecipitation followed by sequencing (ChIP-seq) approach to des...

Descripción completa

Detalles Bibliográficos
Autores principales: Nava, Miguel, Dutta, Pranabananda, Farias-Eisner, Robin, Vadgama, Jaydutt V., Wu, Yanyuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435657/
https://www.ncbi.nlm.nih.gov/pubmed/30914750
http://dx.doi.org/10.1038/s41598-019-41672-6
_version_ 1783406681005228032
author Nava, Miguel
Dutta, Pranabananda
Farias-Eisner, Robin
Vadgama, Jaydutt V.
Wu, Yanyuan
author_facet Nava, Miguel
Dutta, Pranabananda
Farias-Eisner, Robin
Vadgama, Jaydutt V.
Wu, Yanyuan
author_sort Nava, Miguel
collection PubMed
description NGS (Next Generation Sequencing) technologies allows us to determine key gene expression signatures that correlate with resistance (and responsiveness) to anti-cancer therapeutics. We have undertaken a transcriptomic and chromatin immunoprecipitation followed by sequencing (ChIP-seq) approach to describe differences in gene expression and the underlying chromatin landscape between two representative HER2+ cell lines, one of which is sensitive (SKBR3) and the other which is resistant (JIMT1) to trastuzumab. We identified differentially expressed genes (DEGs) and differentially expressed transcripts (DETs) between SKBR3 and JIMT1 cells. Several of the DEGs are components of the Polycomb Repressing Complex 2 (PRC2), and they are expressed higher in JIMT1 cells. In addition, we utilized ChIP-seq to identify H3K18ac, H3K27ac and H3K27me3 histone modifications genome-wide. We identified key differences of H3K18ac and H3K27ac enrichment in regulatory regions, found a correlation between these modifications and differential gene expression and identified a transcription factor binding motif for LRF near these modifications in both cell lines. Lastly, we found a small subset of genes that contain repressive H3K27me3 marks near the gene body in SKBR3 cells but are absent in JIMT1. Taken together, our data suggests that differential gene expression and trastuzumab responsiveness in JIMT1 and SKBR3 is determined by epigenetic mechanisms.
format Online
Article
Text
id pubmed-6435657
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-64356572019-04-02 Utilization of NGS technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance Nava, Miguel Dutta, Pranabananda Farias-Eisner, Robin Vadgama, Jaydutt V. Wu, Yanyuan Sci Rep Article NGS (Next Generation Sequencing) technologies allows us to determine key gene expression signatures that correlate with resistance (and responsiveness) to anti-cancer therapeutics. We have undertaken a transcriptomic and chromatin immunoprecipitation followed by sequencing (ChIP-seq) approach to describe differences in gene expression and the underlying chromatin landscape between two representative HER2+ cell lines, one of which is sensitive (SKBR3) and the other which is resistant (JIMT1) to trastuzumab. We identified differentially expressed genes (DEGs) and differentially expressed transcripts (DETs) between SKBR3 and JIMT1 cells. Several of the DEGs are components of the Polycomb Repressing Complex 2 (PRC2), and they are expressed higher in JIMT1 cells. In addition, we utilized ChIP-seq to identify H3K18ac, H3K27ac and H3K27me3 histone modifications genome-wide. We identified key differences of H3K18ac and H3K27ac enrichment in regulatory regions, found a correlation between these modifications and differential gene expression and identified a transcription factor binding motif for LRF near these modifications in both cell lines. Lastly, we found a small subset of genes that contain repressive H3K27me3 marks near the gene body in SKBR3 cells but are absent in JIMT1. Taken together, our data suggests that differential gene expression and trastuzumab responsiveness in JIMT1 and SKBR3 is determined by epigenetic mechanisms. Nature Publishing Group UK 2019-03-26 /pmc/articles/PMC6435657/ /pubmed/30914750 http://dx.doi.org/10.1038/s41598-019-41672-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nava, Miguel
Dutta, Pranabananda
Farias-Eisner, Robin
Vadgama, Jaydutt V.
Wu, Yanyuan
Utilization of NGS technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance
title Utilization of NGS technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance
title_full Utilization of NGS technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance
title_fullStr Utilization of NGS technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance
title_full_unstemmed Utilization of NGS technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance
title_short Utilization of NGS technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance
title_sort utilization of ngs technologies to investigate transcriptomic and epigenomic mechanisms in trastuzumab resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435657/
https://www.ncbi.nlm.nih.gov/pubmed/30914750
http://dx.doi.org/10.1038/s41598-019-41672-6
work_keys_str_mv AT navamiguel utilizationofngstechnologiestoinvestigatetranscriptomicandepigenomicmechanismsintrastuzumabresistance
AT duttapranabananda utilizationofngstechnologiestoinvestigatetranscriptomicandepigenomicmechanismsintrastuzumabresistance
AT fariaseisnerrobin utilizationofngstechnologiestoinvestigatetranscriptomicandepigenomicmechanismsintrastuzumabresistance
AT vadgamajayduttv utilizationofngstechnologiestoinvestigatetranscriptomicandepigenomicmechanismsintrastuzumabresistance
AT wuyanyuan utilizationofngstechnologiestoinvestigatetranscriptomicandepigenomicmechanismsintrastuzumabresistance