PacBio assembly of a Plasmodium knowlesi genome sequence with Hi-C correction and manual annotation of the SICAvar gene family.

Plasmodium knowlesi has risen in importance as a zoonotic parasite that has been causing regular episodes of malaria throughout South East Asia. The P. knowlesi genome sequence generated in 2008 highlighted and confirmed many similarities and differences in Plasmodium species, including a global view of several multigene families, such as the large SICAvar multigene family encoding the variant antigens known as the schizont-infected cell agglutination proteins. However, repetitive DNA sequences are the bane of any genome project, and this and other Plasmodium genome projects have not been immune to the gaps, rearrangements and other pitfalls created by these genomic features. Today, long-read PacBio and chromatin conformation technologies are overcoming such obstacles. Here, based on the use of these technologies, we present a highly refined de novo P. knowlesi genome sequence of the Pk1(A+) clone. This sequence and annotation, referred to as the 'MaHPIC Pk genome sequence', includes manual annotation of the SICAvar gene family with 136 full-length members categorized as type I or II. This sequence provides a framework that will permit a better understanding of the SICAvar repertoire, selective pressures acting on this gene family and mechanisms of antigenic variation in this species and other pathogens.

TGF-ß1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells.

In spite of a large number of transforming growth factor ß1 (TGF-ß1)-regulated genes, the nature of its targets with roles in transformation continues to be poorly understood. Here, we discovered that TGF-ß1 stimulates transcription of metastasis-associated protein 1 (MTA1), a dual master coregulator, in epithelial cells, and that MTA1 status is a determinant of TGF-ß1-induced epithelial-to-mesenchymal transition (EMT) phenotypes. In addition, we found that MTA1/polymerase II/activator protein-1 (AP-1) co-activator complex interacts with the FosB-gene chromatin and stimulates its transcription, and FosB in turn, utilizes FosB/histone deacetylase 2 complex to repress E-cadherin expression in TGF-ß1-stimulated mammary epithelial cells. These findings suggest that TGF-ß1 regulates the components of EMT via stimulating the expression of MTA1, which in turn, induces FosB to repress E-cadherin expression and thus, revealed an inherent function of MTA1 as a target and effector of TGF-ß1 signaling in epithelial cells.

NF-kappaB signaling mediates the induction of MTA1 by hepatitis B virus transactivator protein HBx.

Metastasis-associated protein 1 (MTA1), a master chromatin modifier, has been shown to regulate cancer progression and is widely upregulated in human cancer, including hepatitis B virus-associated hepatocellular carcinomas (HCCs). Here we provide evidence that hepatitis B virus transactivator protein HBx stimulates the expression of MTA1 but not of MTA2 or MTA3. The underlying mechanism of HBx stimulation of MTA1 involves HBx targeting of transcription factor nuclear factor (NF)-kappaB and the recruitment of HBx/p65 complex to the NF-kappaB consensus motif on the relaxed MTA1 gene chromatin. We also discovered that MTA1 depletion in HBx-expressing cells severely impairs the ability of HBx to stimulate NF-kappaB signaling and the expression of target proinflammatory molecules. Furthermore, the presence of HBx in HBx-infected HCCs correlated well with increased MTA1 and NF-kappaB-p65. Collectively, these findings revealed a previously unrecognized integral role of MTA1 in HBx stimulation of NF-kappaB signaling and consequently, the expression of NF-kappaB targets gene products with functions in inflammation and tumorigenesis.