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Loss of Apc impairs Lgr5+ intestinal stem cell fate programs [RNA-seq]

ABSTRACT: Loss of APC is the main driving alteration associated with colorectal cancer (CRC) development. We investigate the immediate outcome of this genetic event on the transcriptomic and DNA methylation profiles of Lgr5+ intestinal stem cells (ISCs), considered as the cell-of-origin of CRC. RNA-seq analyses show that the sequential deletion of Apc alleles has a rapid impact on the transcriptional profiles of ISCs. Indeed, Apc loss-of-function dictates an altered cell fate program at transcriptional level, resuting in an impaired commitment of those cells to differentiation. Reduced-representation bisufite sequencing (RRBS) on the genomic DNA (gDNA) also shows that focal alterations occur in the DNA methylations profiles of ISCs at this stage, and functionally contribute to altered cell fate in those cells. This study sheds light on the earliest events in CRC development, proving evidences on the role exerted by DNA methylation changes associated with Apc inactivation in the homeostatic rupture at CRC initation.

ORGANISM(S): Mus musculus

PROVIDER: GSE123005 | GEO | 2020/03/22

REPOSITORIES: GEO

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Loss of Apc impairs Lgr5+ intestinal stem cell fate programs [RRBS]

Project description:Loss of APC is the main driving alteration associated with colorectal cancer (CRC) development. We investigate the immediate outcome of this genetic event on the transcriptomic and DNA methylation profiles of Lgr5+ intestinal stem cells (ISCs), considered as the cell-of-origin of CRC. RNA-seq analyses show that the sequential deletion of Apc alleles has a rapid impact on the transcriptional profiles of ISCs. Indeed, Apc loss-of-function dictates an altered cell fate program at transcriptional level, resuting in an impaired commitment of those cells to differentiation. Reduced-representation bisufite sequencing (RRBS) on the genomic DNA (gDNA) also shows that focal alterations occur in the DNA methylations profiles of ISCs at this stage, and functionally contribute to altered cell fate in those cells. This study sheds light on the earliest events in CRC development, proving evidences on the role exerted by DNA methylation changes associated with Apc inactivation in the homeostatic rupture at CRC initation.

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Project description:A collection of genetically engineered mouse models (GEMM) of colorectal cancer (CRC) were created, and primary tumors from these GEMMs were analyzed. Primary CRC tumors from these GEMMs were genotyped to confirm that they contain the core genetic lesions of interest, including APC, P53, KRAS, and BRAF. Primary tumors from GEMMs with combinations of lesions of interest were analyzed by whole genome expression, and their expression profiles were compared to determine how they segregate. Signatures were then generated from GEMM tumors of interest and compared to human clinical datasets with expression and outcome data. Primary tumors from CRC GEMMs with different combinations of mutant alleles of interested were generated and analyzed. Alleles include mutant forms of APC (A), P53 (P), KRAS (K) and BRAF (B).

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