Structural insights into acetylated histone ligand recognition by the BDP1 bromodomain of Plasmodium falciparum

Singh, Ajit; Phillips, Margaret; Alkrimi, Saleh; Tonelli, Marco; Boyson, Samuel P.; Malone, Kiera L.; Nix, Jay C.; Glass, Karen C.

doi:10.1016/j.ijbiomac.2022.10.247

“…1E ). The crystal structure of the bromodomain of P. falciparum PfBDP1 has recently been determined (PDB: 7M97) ( 24 ) and closely matches that of the predicted structure of the bromodomain in TgBDP1. The conserved sequence and structure of the predicted TgBDP1 bromodomain suggest that TgBDP1 is a functional acetyl-lysine reader.…”

Section: Resultsmentioning

confidence: 56%

“…The P. falciparum homologue, PfBDP1, did not display a strong affinity for acetylated histone H3 peptide, even when multiple lysine residues were acetylated, suggesting that acetylated H3 is not important for complex recruitment. However, PfBDP1 has high binding affinity for acetylated histones H4, H2b.Z, and H2a.z ( 24 , 46 ), particularly when multiple acetyl marks are present, suggesting that the PfBDP1/BDP2 complex is recruited to highly acetylated chromatin rather than a specific acetylated histone residue. Additional studies will be needed to determine if this is also the case in Toxoplasma .…”

Section: Discussionmentioning

confidence: 99%

An apicomplexan bromodomain protein, TgBDP1, associates with diverse epigenetic factors to regulate essential transcriptional processes in Toxoplasma gondii

Fleck

¹

,

McNutt

²

,

Chu

³

et al. 2023

mBio

5

0

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The protozoan pathogen Toxoplasma gondii relies on tight regulation of gene expression to invade and establish infection in its host. The divergent gene regulatory mechanisms of Toxoplasma and related apicomplexan pathogens rely heavily on regulators of chromatin structure and histone modifications. The important contribution of histone acetylation for Toxoplasma in both acute and chronic infection has been demonstrated, where histone acetylation increases at active gene loci. However, the direct consequences of specific histone acetylation marks and the chromatin pathway that influences transcriptional regulation in response to the modification are unclear. As a reader of lysine acetylation, the bromodomain serves as a mediator between the acetylated histone and transcriptional regulators. Here we show that the bromodomain protein, TgBDP1, which is conserved among Apicomplexa and within the Alveolata superphylum, is essential for Toxoplasma asexual proliferation. Using cleavage under targets and tagmentation, we demonstrate that TgBDP1 is recruited to transcriptional start sites of a large proportion of parasite genes. Transcriptional profiling during TgBDP1 knockdown revealed that loss of TgBDP1 leads to major dysregulation of gene expression, implying multiple roles for TgBDP1 in both gene activation and repression. This is supported by interactome analysis of TgBDP1 demonstrating that TgBDP1 forms a core complex with two other bromodomain proteins and an ApiAP2 factor. This core complex appears to interact with other epigenetic factors such as nucleosome remodeling complexes. We conclude that TgBDP1 interacts with diverse epigenetic regulators to exert opposing influences on gene expression in the Toxoplasma tachyzoite. IMPORTANCE Histone acetylation is critical for proper regulation of gene expression in the single-celled eukaryotic pathogen Toxoplasma gondii . Bromodomain proteins are “readers” of histone acetylation and may link the modified chromatin to transcription factors. Here, we show that the bromodomain protein TgBDP1 is essential for parasite survival and that loss of TgBDP1 results in global dysregulation of gene expression. TgBDP1 is recruited to the promoter region of a large proportion of parasite genes, forms a core complex with two other bromodomain proteins, and interacts with different transcriptional regulatory complexes. We conclude that TgBDP1 is a key factor for sensing specific histone modifications to influence multiple facets of transcriptional regulation in Toxoplasma gondii .

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“…1E). The crystal structure of the bromodomain of Plasmodium falciparum PfBDP1 has recently been determined (PDB: 7M97) (24) and closely matches that of the predicted structure of the bromodomain in TgBDP1. The conserved sequence and structure of the predicted TgBDP1 bromodomain suggests that TgBDP1 is a functional acetyllysine reader.…”

Section: Resultsmentioning

confidence: 58%

“…The P. falciparum homologue, PfBDP1 did not display strong affinity for acetylated histone H3 peptide, even when multiple lysine residues were acetylated, suggesting that acetylated H3 is not important for complex recruitment. However, PfBDP1 has high binding affinity for acetylated histones H4, H2b.Z and H2a.z (24,44), particularly when multiple acetyl marks are present, suggesting that the PfBDP1/BDP2 complex is recruited to highly acetylated chromatin, rather than a specific acetylated histone residue. Additional studies will be needed to determine if this is also the case in Toxoplasma .…”

Section: Discussionmentioning

confidence: 99%

An apicomplexan bromodomain, TgBDP1 associates with diverse epigenetic factors to regulate essential transcriptional processes inToxoplasma gondii

Fleck

¹

,

McNutt

²

,

Chu

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

The protozoan pathogen Toxoplasma gondii relies on tight regulation of gene expression to invade and establish infection in its host. The divergent gene regulatory mechanisms of Toxoplasma and related apicomplexan pathogens rely heavily on regulators of chromatin structure and histone modifications. The important contribution of histone acetylation for Toxoplasma in both acute and chronic infection has been demonstrated, where histone acetylation increases at active gene loci. However, the direct consequences of specific histone acetylation marks and the chromatin pathway that influences transcriptional regulation in response to the modification is unclear. As a reader of lysine acetylation, the bromodomain serves as a mediator between the acetylated histone and transcriptional regulators. Here we show that the bromodomain protein TgBDP1 which is conserved amongst Apicomplexa and within the Alveolata superphylum, is essential for Toxoplasma asexual proliferation. Using CUT&TAG we demonstrate that TgBDP1 is recruited to transcriptional start sites of a large proportion of parasite genes. Transcriptional profiling during TgBDP1 knockdown revealed that loss of TgBDP1 leads to major dysregulation of gene expression, implying multiple roles for TgBDP1 in both gene activation and repression. This is supported by interactome analysis of TgBDP1 demonstrating that TgBDP1 forms a core complex with two other bromodomain proteins and an ApiAP2 factor. This core complex appears to interact with other epigenetic factors such as nucleosome remodelling complexes. We conclude that TgBDP1 interacts with diverse epigenetic regulators to exert opposing influences on gene expression in the Toxoplasma tachyzoite.

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Advances in personalized epigenetics in infectious diseases

Arumugam,

Dayaram,

Gokul

et al. 2024

Personalized Epigenetics

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Structural insights into acetylated histone ligand recognition by the BDP1 bromodomain of Plasmodium falciparum

Cited by 6 publications

References 47 publications

An apicomplexan bromodomain protein, TgBDP1, associates with diverse epigenetic factors to regulate essential transcriptional processes in Toxoplasma gondii

An apicomplexan bromodomain protein, TgBDP1, associates with diverse epigenetic factors to regulate essential transcriptional processes in Toxoplasma gondii

An apicomplexan bromodomain, TgBDP1 associates with diverse epigenetic factors to regulate essential transcriptional processes inToxoplasma gondii

Advances in personalized epigenetics in infectious diseases

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