한빛사논문
- 조회1,729
Harshabad Singh1,2, Kyungsik Ha3, Jason L. Hornick4, Shariq Madha1, Paloma Cejas1, Kunal Jajoo2, Pratik Singh1,2, Paz Polak5, Hwajin Lee3,¶, Ramesh A. Shivdasani1,2,6¶
1Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of 2Medicine and 4Pathology, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; 3Biomedical Knowledge Engineering Laboratory, Seoul National University, Seoul, Korea; 5Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; 6Harvard Stem Cell Institute, Cambridge, MA 02138, USA
¶Correspondence
Abstract
Background & Aims
Tissue metaplasia is uncommon in adults because established cis-element programs resist rewiring. In Barrett’s esophagus, the distal esophageal mucosa acquires predominantly intestinal character, with notable gastric features, and is predisposed to develop invasive cancers. We sought to understand the chromatin underpinnings of Barrett’s metaplasia and why it commonly displays simultaneous gastric and intestinal properties.
Methods
We profiled cis-regulatory elements with active histone modifications in primary human biopsy materials using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Mutations in Barrett’s esophagus were examined in relation to tissue-specific enhancer landscapes using a random-forest machine learning algorithm. We also profiled open chromatin at single-cell resolution in primary Barrett’s biopsy specimens using the assay for transposase-accessible chromatin (ATAC-seq). We used one- and two-color immunohistochemistry to examine protein expression of tissue-restricted genes.
Results
Barrett’s esophagus bears epigenome fingerprints of human stomach and intestinal columnar, but not esophageal squamous, epithelia. Mutational patterns were best explained as arising on the epigenome background of active gastric cis-elements, supporting the view that adjoining stomach epithelium is a likely tissue source. Individual cells in Barrett’s metaplasia co-express gastric and intestinal genes, reflecting concomitant chromatin access at enhancers ordinarily restricted to one or the other epithelium. Protein expression of stomach-specific mucins, CLDN18, and a novel gastric marker, ANXA10, revealed extensive tissue and sub-clonal heterogeneity of dual stomach-intestinal cell states.
Conclusions
These findings reveal mixed and dynamic tissue-restricted chromatin states and phenotypic heterogeneity in Barrett’s esophagus. Pervasive intra-gland variation argues against stem-cell governance of this phenotype.
논문정보
- Research article
- 2021년 06월 (BRIC 등록일 2021-06-08)
- 국내(교신)+국외 연구진
- 의약학 > 유전 및 유전체의학
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