Gene regulation in Cryptosporidium: New insights and unanswered questions

Abstract

Parasites of the genus Cryptosporidium have evolved to have a highly compact genome of ∼9.1 Mb. The mechanisms that regulate gene expression in Cryptosporidium spp. remain incompletely understood at all levels, including chromatin accessibility, transcription factor activation and repression and RNA processing. This review discusses possible mechanisms of gene regulation in Cryptosporidium spp., including histone modifications, cis regulatory elements, transcription factors and non-coding RNAs. Cryptosporidium spp. are among the most basal branching apicomplexans and existing evidence suggests that they diverge from other members of their phylum via retention of the E2F/DP1 transcription factor family, and the recent discovery that C. parvum produces polycistronic transcripts. Most of what we know about gene regulation in the genus Cryptosporidium is based on sequence conservation and homology with other members of the phylum Apicomplexa, and in some cases, more distant eukaryotes. Very few putative gene regulatory components identified in Cryptosporidium spp. are supported by experimental confirmation. This review summarizes what we know about gene regulation in Cryptosporidium spp. and identifies gaps in our current understanding.

Keywords: Apicomplexa; Epigenetics; Non-coding RNA; Polycistronic transcription; Transcription factor.

Created in BioRender. Gunasekera, S. (2025) https://BioRender.com/0p0fo7f.

Fig. 1

Enzymes in C. parvum with possible roles in post-translational modifications of histone tails. A Schematic diagram of chromatin and histone octamer structure. BCryptosporidium parvum does possess GNAT family HAT orthologs but the HAT pathway has been shaded grey since none have been functionally confirmed. CCryptosporidium parvum encodes three RPD3 family HDACs which have been demonstrated to bind histone tails, and one Sir2 family HDAC that has not been experimentally confirmed (shown in grey). D Seven out of eight SET family proteins in C. parvum were identified as putative histone methyltransferases (Sawant et al., 2022). Created in Biorender. Gunasekera, S. (2025) https://BioRender.com/wp3u43V.

Fig. 2

Possible transcription factors in C. parvum that may have a role in gene regulation. Little is known about the entire transcription factor complexes that regulate gene expression in Cryptosporidium spp. Schematic diagrams representing our understanding of ApiAP2 transcription factor activation of gene expression in Cryptosporidium spp. (A), E2F/DP transcription factor activity in eukaryotes (B), possible Myb/SANT gene regulation in Cryptosporidium spp. (C), and possible role of C2H2 ZnF in Cryptosporidium spp. gene regulation (D). Only one transcription factor protein for each scenario is shown but several may be present. Created in BioRender. Gunasekera, S. (2025) https://BioRender.com/odz641n.

Fig. 3

Possible epitranscriptomic modifications that Cryptosporidium spp. could utilize for gene regulation. Small RNAs are shown in blue, methyl groups are shown in red, modified regions of target RNAs are shown in green. Created in BioRender. Gunasekera, S. (2025) https://BioRender.com/9bqfw87.

Fig. 4

The structure of uORFs and polycistronic transcripts. Schematic diagram of a transcript with an uORF (not yet reported in Cryptosporidium spp.) (A), and a polycistronic transcript, recently reported in C. parvum (Xiao et al., 2025) (B). Created in BioRender. Gunasekera, S. (2025) https://BioRender.com/Uizemxv.