Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to oesophageal adenocarcinoma

Abstract

Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths. Barrett's oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the molecular events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin to directly regulate cell cycle genes specifically in OAC cells. This new KLF5 target gene programme has potential prognostic significance as high levels correlate with poorer patient survival. Thus, the repurposing of KLF5 for novel regulatory activity in OAC provides new insights into the mechanisms behind disease progression.

Regulatory chromatin rewiring promotes metabolic switching during adaptation to oncogenic receptor tyrosine kinase inhibition

“…ChIP-qPCR and ChIP-seq was performed as described previously [ 25 ]. Primers for ChIP-qPCR are listed in Supplementary Table 5 .…”

“…Patient tissue RNA-seq data was obtained from: E-MTAB-4054 [ 30 ] and the OCCAMS consortium (EGAD00001007496). Human tissue ATAC-seq data was obtained from: E-MTAB-5169 [ 28 ], E-MTAB-6751 [ 24 ], E-MTAB-8447 [ 25 ] and The Cancer Genome Atlas OAC ATAC-seq data were obtained from the GDC data portal (portal.gdc.cancer.gov; [ 71 ]).…”

“…OE19 HNF4A ChIP-seq data was obtained from E-MTAB-6858 [ 24 ]. OE19 siERBB2 RNA-seq data was obtained from E-MTAB-8579 [ 25 ]. OE19 H3K27ac ChIP-seq data was obtained from NCBI SRA SRP201335 [ 26 ].…”

“…However, at the pathway level, components of the receptor tyrosine kinase (RTK) driven pathways are frequently mutated in OAC (60–76%; [ 22 , 23 ]), typified by relatively high frequency amplifications and mutations of the RTK ERRB2 (ranging from 18–32% tumours; [ 22 , 23 ]). At the epigenetic level, the accessible chromatin landscape of BO is vastly different to the surrounding normal oesophageal tissue and this landscape is further altered during the transition to OAC [ 24 , 25 ]. These chromatin changes are accompanied by alterations to the transcriptional regulatory networks, with many changes to transcription factor activity being common to BO and OAC, including transcription factors like HNF4A, GATA6, FOXA, HNF1B and PPARG [ 24 , 26 , 27 ].…”

“…These chromatin changes are accompanied by alterations to the transcriptional regulatory networks, with many changes to transcription factor activity being common to BO and OAC, including transcription factors like HNF4A, GATA6, FOXA, HNF1B and PPARG [ 24 , 26 , 27 ]. Conversely, other transcription factors appear more dominant in OAC such as AP1 [ 28 ] or their regulatory activity is repurposed and directed to alternative transcriptional programmes as exemplified by KLF5 [ 25 ]. However, it is unclear how the deregulated RTK pathways impact on these gene regulatory networks.…”