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Katherine A. Jones

 

Katherine A. Jones

Katherine A. Jones

Professor
Regulatory Biology Laboratory

"The search for unified theories is not limited to those who study physics or the cosmos. A 'unified theory' of gene expression is required to explain how transcription—the complex, multistep process that generates messenger RNA copies from protein-encoding genes—is coordinated within the cell."

If stretched out, the DNA of a single human cell would form a very thin thread about six feet in length. To fit such a long molecule inside a cell's nucleus and keep everything neatly organized, the DNA is threaded around histone proteins and coiled up in a highly condensed structure called chromatin. When genes are actively transcribed, the tightly folded chromatin must open up just enough to give the transcriptional complex access to the DNA. Recently, Jones and her team discovered that Spt6, a histone "chaperone" protein that functions to move nucleosomal histones out of the path of the oncoming transcription complex, interacts directly with RNA polymerase II (RNAPII), the central catalytic enzyme responsible for copying genes to RNA. Surprisingly, the complex assembled by Spt6 on RNAPII does not include factors required for transcription, but instead includes proteins like REF1/Aly, which transfer onto the newly made RNA to negotiate its export from the nucleus, and Rrp6, a subunit of the nuclear "exosome" mRNA degradation machinery, which travels with the transcription complex to destroy any aberrantly formed nascent RNA.

They discovered that this complex also plays an important role in regulating the chromatin state of actively expressed genes. In particular, the Spt6 complex recruits the Huntingtin-interacting protein, HYPB/Setd2, which creates a specific pattern of methylated histones that commonly marks the chromatin of active genes. This process would ensure that the chromosomal DNA structure is not disrupted by ongoing transcription. These findings raise the interesting question of whether proteins involved in mRNA biosynthesis and export have redundant roles in chromatin modification, or vice versa. In this respect, it is interesting that enzymes that mark active gene chromatin by ubiquitination have also been linked with mRNA export, in part by physically tethering the active gene to the nuclear pore. Future studies of the Spt6 complex on RNAPII will help explain the mysterious processes through which transcription is integrated with the many other diverse steps, such as chromatin remodeling and modification and mRNA export, that are required for mammalian gene expression.

Lab Photo

Left to right:
Yupeng Chen, Lirong Zhang, Harsh Kavi, Caroline Kemp, Katherine Jones, Vanessa Bres, Katherine So, Sunnie Yoh, Tomonori Yoshida, Nevin Murthy

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Katherine A. Jones

Faculty

Katherine A. Jones

Katherine A. Jones

Professor
Regulatory Biology Laboratory

Transcription Mechanisms in Human Disease

Our laboratory is interested in the transcriptional mechanisms responsible for rapid induction of mammalian genes. We are currently focused on the control of RNAPII elongation at the HIV-1 promoter by the HIV-1 Tat protein, which acts through an RNA element to recruit the host cell P-TEFb (CycT1:CDK9) elongation factor. We recently found that an alternative splicing factor, SKIP, also regulates RNAPII transcription elongation. SKIP associates with P-TEFb and is required for Tat activation, and current studies are seeking to identify how SKIP and associated factors control transcription elongation at HIV-1 and cellular genes. We are also examining how non-coding regulatory RNAs control transcription elongation and P-TEFb activity, and how transcription elongation is coupled to specific chromatin modifications, including H3K4 methylation and H3K36 methylation in vivo. These studies should help us better understand the intricate links between transcription elongation, nucleosome methylation, and RNA processing and export in human cells.

Another area of interest is the mechanisms that regulate Wnt and Notch signaling in human colon cancers. We recently showed that the Wnt co-activator, beta-catenin, interacts with factors required for H3K4 methylation of target genes, and that the APC tumor suppressor functions to down-regulate beta-catenin transcription at target genes. APC represses transcription through recruiting the CtBP co-repressor, and also promotes the degradation and turnover of beta-catenin at target genes. Interestingly, mutant APC proteins, which are found in human colon cancers, are unable to bind CtBP and unable to repress Wnt target genes, such as c-Myc, in vivo. Beta-catenin and other co-regulators appear in a cyclic fashion at Wnt genes in vivo, in a manner that requires APC-mediated turnover of the complex. We are interested in assessing whether the cyclic recruitment of Wnt coregulators directs cyclic transcription, and how cycling of Wnt transcription may affect Notch target genes. We recently found that the Notch co-activator Mastermind, co-ordinates transcriptional activation with turnover of the Notch intracellular domain activator. This is controlled by binding of Mastermind to the CDK8, a kinase that phosphorylates the C-terminal PEST regulatory domain of Notch. Recent studies indicate that Notch transcription is strongly regulated at the level of transcription elongation through P-TEFb and SKIP, and are studying how these factors are recruited and function in response to Notch signaling.

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