Dataset Information

Cohesin is involved in transcriptional repression of invasion-related genes

ABSTRACT: The most virulent human malaria parasite, Plasmodium falciparum, has a complex life cycle between its human host and mosquito vector. Each stage is driven by a specific transcriptional program, but with a relatively high ratio of genes to specific transcription factors, it is unclear how genes are activated or silenced at specific times. The P. falciparum genome is relatively euchromatic compared to the mammalian genome, except for specific genes that are uniquely heterochromatinized via HP1. There seems to be an association between gene activity and spatial organization; however, the molecular mechanisms behind genome organization are unclear. While P. falciparum lacks lamins and CTCF – key metazoan genome-organizing proteins – it does have all core components of the cohesin complex. In other eukaryotes, cohesin is involved in sister chromatid cohesion, transcription, and genome organization. To investigate the role of cohesin in P. falciparum, we combined genome editing, mass-spectrometry, chromatin immunoprecipitation and sequencing (ChIP-seq), and RNA sequencing to functionally characterize the cohesin subunit Structural Maintenance of Chromosomes protein 3 (SMC3). SMC3 knockdown in early stages of the intraerythrocytic developmental cycle (IDC) resulted in significant up-regulation of a subset of genes involved in erythrocyte egress and invasion, which are normally expressed at later stages. ChIP-seq of SMC3 revealed that over the IDC, enrichment at the promoter regions of these genes inversely correlates with their expression. These data suggest that SMC3 binding helps to repress specific genes until their appropriate time of expression, revealing a new mode of gene repression in P. falciparum.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell

DISEASE(S): Plasmodium Falciparum Malaria

SUBMITTER: AMEYA SINHA

LAB HEAD: Peter R. Preiser

PROVIDER: PXD035225 | Pride | 2023-10-04

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20210127_AS_IP_1203500_DSP_Rep1-_1_.mgf	Mgf
	20210127_AS_IP_1203500_DSP_Rep1-_1_.msf	Msf
	20210127_AS_IP_1203500_DSP_Rep1-_1_.mzML	Mzml
	20210127_AS_IP_1203500_DSP_Rep1-_1_.mzid.gz	Mzid
	20210127_AS_IP_NF54_DSP_Rep1.raw	Raw

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Publications

Cohesin contributes to transcriptional repression of stage-specific genes in the human malaria parasite.

Rosa Catarina C Singh Parul P Chen Patty P Sinha Ameya A Claës Aurélie A Preiser Peter R PR Dedon Peter C PC Baumgarten Sebastian S Scherf Artur A Bryant Jessica M JM

EMBO reports 20230818 10

The complex life cycle of the human malaria parasite, Plasmodium falciparum, is driven by specific transcriptional programs, but it is unclear how most genes are activated or silenced at specific times. There is an association between transcription and spatial organization; however, the molecular mechanisms behind genome organization are unclear. While P. falciparum lacks key genome-organizing proteins found in metazoans, it has all core components of the cohesin complex. To investigate the role ...[more]

PMID: 37592911

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Project description:The development of the human malaria parasite Plasmodium falciparum is controlled by coordinated changes in gene expression throughout its complex life cycle, but the corresponding regulatory mechanisms are incompletely understood. To study the relation between genome architecture and gene regulation in Plasmodium, we studied the genome structure of P. falciparum at three time points during its erythrocytic (asexual) cycle. Using chromosome conformation capture coupled with next-generation sequencing technology (Hi-C), we obtained high-resolution chromosomal contact maps, which we then used to construct a consensus three-dimensional genome structure for each time point. We observe strong clustering of centromeres, telomeres, ribosomal DNA and virulence genes, resulting in a complex architecture that cannot be explained by a simple volume exclusion model. Internal virulence gene clusters appear to be an important factor in shaping the genome architecture as they exhibit domain-like structures similar to topological domains in mammalian genomes. Midway during the cell cycle, at the highly transcriptionally active trophozoite stage, the genome adopts a more open chromatin structure with increased chromosomal intermingling. In addition, we observed reduced expression of genes located in spatial proximity to the repressive subtelomeric center, and colocalization of distinct groups of parasite-specific genes with coordinated expression profiles. Overall, our results are indicative of a strong association between the P. falciparum spatial genome organization and gene expression. Understanding the molecular processes involved in genome conformation dynamics could contribute to the discovery of novel antimalarial strategies. Analysis of the spatial organization of the P. falciparum genome at three stages of the erythrocytic cycle using chromosome conformation capture coupled with next generation sequencing (Hi-C). As a control, we included one sample for which chromatin contacts were not preserved by crosslinking of DNA and proteins.