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TISSUE-LOCATION SPECIFIC TRANSCRIPTIONAL PROGRAMS IN COLON DETERMINE MOLECULAR DEPENDENCIES FOR TUMOR INITIATION [ChIP-Seq]

ABSTRACT: TISSUE-LOCATION SPECIFIC TRANSCRIPTIONAL PROGRAMS IN COLON DETERMINE MOLECULAR DEPENDENCIES FOR TUMOR INITIATION [ChIP-Seq]

PROVIDER: PRJNA903915 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22362200_1.fastq.gz	Fastqsanger.gz
	SRR22362200_2.fastq.gz	Fastqsanger.gz
	SRR22362201_1.fastq.gz	Fastqsanger.gz
	SRR22362201_2.fastq.gz	Fastqsanger.gz
	SRR22362202_1.fastq.gz	Fastqsanger.gz

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TISSUE-LOCATION SPECIFIC TRANSCRIPTIONAL PROGRAMS IN COLON DETERMINE MOLECULAR DEPENDENCIES FOR TUMOR INITIATION

Project description:TISSUE-LOCATION SPECIFIC TRANSCRIPTIONAL PROGRAMS IN COLON DETERMINE MOLECULAR DEPENDENCIES FOR TUMOR INITIATION

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TISSUE-LOCATION SPECIFIC TRANSCRIPTIONAL PROGRAMS IN COLON DETERMINE MOLECULAR DEPENDENCIES FOR TUMOR INITIATION [RNA-Seq]

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TISSUE-LOCATION SPECIFIC TRANSCRIPTIONAL PROGRAMS IN COLON DETERMINE MOLECULAR DEPENDENCIES FOR TUMOR INITIATION [ChIP-Seq]

Project description:It is not known why cancers arising in anatomically distinct locations but within the same tissue type can exhibit stark differences in molecular, pathological and clinical features. Cancers arising in proximal and distal sites of the colon are emblematic of these above differences as the proximal and distal colon cancers harbor differences in key molecular features, with BRAFV600E oncogene predominantly occurring in proximal colon cancers in the context of the increased promoter DNA methylation phenotype (CIMP-high), while distal colon cancers lack these molecular features. We determined the molecular basis of tissue-location specificity of driver mutations using normal mouse derived organoid models for colon cancer initiation. We show that the homeobox transcription factor, Cdx2, which is downregulated by DNA methylation in proximal colon cancers, plays distinct roles in regulating stem cell and differentiation in proximal compared to distal colon stem cells. Loss of Cdx2 altered the differentiation and stem cell programs and result in transformation by BRAFV600E specifically in the proximal but not distal colon stem cells. Analyses of RNA expression and Cdx2-binding to target genomic regions revealed that Cdx2 was a key effector of the transcriptional response to differentiation cues in proximal colon cells. This proximal colon-specific transcriptional program concurrently is tumor suppressive, and its loss sufficiently creates permissive state for oncogenic-BRAF mutations. The transcriptional program associated with Cdx2 loss in mouse proximal organoids matches that of human proximal colon cancers with downregulated CDX2 expression due to epigenetic silencing. Our analyses reveal that developmental and lineage-restricted transcription factors maintain tissue-location specific transcriptional programs which create critical dependencies for tumor initiation.

2023-12-12 | GSE218479 | GEO

TISSUE-LOCATION SPECIFIC TRANSCRIPTIONAL PROGRAMS IN COLON DETERMINE MOLECULAR DEPENDENCIES FOR TUMOR INITIATION [RNA-Seq]

2023-12-12 | GSE218480 | GEO

TISSUE-LOCATION SPECIFIC TRANSCRIPTIONAL PROGRAMS IN COLON DETERMINE MOLECULAR DEPENDENCIES FOR TUMOR INITIATION

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-12 | GSE218482 | GEO

Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.

Project description:Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAFV600E-driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development.

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mRNA Location and Translation Rate Determine Protein Targeting to Dual Destinations

Project description:mRNA Location and Translation Rate Determine Protein Targeting to Dual Destinations

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mRNA Location and Translation Rate Determine Protein Targeting to Dual Destinations

Project description:Numerous proteins are targeted to two or multiple subcellular destinations where they exert distinct functional consequences. The balance between such differential targeting is thought to be determined post-translationally, relying on protein sorting mechanisms. Here, we show that protein targeting can additionally be determined by mRNA location and translation rate. Our model, the NET1 protein, distributes between the nucleus and cytosol and functions in cell motility. N-terminal NLSs and an internal PH domain competitively determine NET1 distribution. Peripheral localization of the NET1 mRNA and fast translation lead to higher cytosolic retention through the PH domain. By contrast, perinuclear mRNA location and/or slower translation rate favor nuclear targeting through importin β1. NET1 mRNA location is modulated by physiological stimuli and profoundly impacts NET1 function in cell motility. Indeed, perinuclear NET1 mRNA localization causes reduced RhoA activity, impedes focal adhesion maturation and results in slower cell migration to an extent similar as that observed upon knockdown of NET1 expression. Overall, these results reveal that the location of protein synthesis and the rate of translation elongation act in coordination to influence the ability of competing domains within a polypeptide to determine protein distribution and function.

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Project description:For survival, autophagy is a crucial intracellular self-degradation process to provide energy sources, helping adapt to nutrient deprivation. Although nutrient availability is a key determinant of autophagy initiation, it remains elusive underlying mechanism(s) of perceiving nutritional scarcity by which cells timely turn on autophagy as the last self-destructive process for energy supply. Here, we showed that PKA-dependent lipolysis can block the initiation of futile autophagy during short-term nutritional deprivation by repressing AMPK. Using Raman microscopy imaging and metabolomics, we found that autophagy occurred by reduction in available free fatty acids (FFAs) for energy sources. By modulating genes involved in lipolysis and fatty acid oxidation, we found that the use of lipolysis-derived FFAs precedes autophagy initiation. The dysregulated autophagy suppression during short-term fasting decreased motility and lifespan extension of worms. Taken together, these data suggest that PKA is a pivotal factor to orchestrate sophisticated catabolic pathways, preferring the use of PKA-mediated lipolytic products to repress futile autophagic degradation during short-term fasting through AMPK inhibition.

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