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Dive into the research topics where Lauren P. Blair is active.

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Featured researches published by Lauren P. Blair.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1

Wenchu Lin; Jian Cao; Jiayun Liu; Michael L. Beshiri; Yuko Fujiwara; Joshua M. Francis; Andrew D. Cherniack; Christoph Geisen; Lauren P. Blair; Mike R. Zou; Xiaohua Shen; Dan Kawamori; Zongzhi Liu; Chiara Grisanzio; Hideo Watanabe; Yoji Andrew Minamishima; Qing Zhang; Rohit N. Kulkarni; Sabina Signoretti; Scott J. Rodig; Roderick T. Bronson; Stuart H. Orkin; David Tuck; Elizaveta V. Benevolenskaya; Matthew Meyerson; William G. Kaelin; Qin Yan

Aberrations in epigenetic processes, such as histone methylation, can cause cancer. Retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) can demethylate tri- and dimethylated lysine 4 in histone H3, which are epigenetic marks for transcriptionally active chromatin, whereas the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor promotes H3K4 methylation. Previous studies suggested that inhibition of RBP2 contributed to tumor suppression by the retinoblastoma protein (pRB). Here, we show that genetic ablation of Rbp2 decreases tumor formation and prolongs survival in Rb1+/− mice and Men1-defective mice. These studies link RBP2 histone demethylase activity to tumorigenesis and nominate RBP2 as a potential target for cancer therapy.


Cancers | 2011

Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer

Lauren P. Blair; Jian Cao; Mike Ran Zou; Joyce Sayegh; Qin Yan

Similar to genetic alterations, epigenetic aberrations contribute significantly to tumor initiation and progression. In many cases, these changes are caused by activation or inactivation of the regulators that maintain epigenetic states. Here we review our current knowledge on the KDM5/JARID1 family of histone demethylases. This family of enzymes contains a JmjC domain and is capable of removing tri- and di- methyl marks from lysine 4 on histone H3. Among these proteins, RBP2 mediates drug resistance while JARID1B is required for melanoma maintenance. Preclinical studies suggest inhibition of these enzymes can suppress tumorigenesis and provide strong rationale for development of their inhibitors for use in cancer therapy.


Journal of Biological Chemistry | 2013

Identification of Small Molecule Inhibitors of Jumonji AT-Rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High-throughput Screen

Joyce Sayegh; Jian Cao; Mike Ran Zou; Alfonso Morales; Lauren P. Blair; Michael Norcia; Denton Hoyer; Alan J. Tackett; Jane S. Merkel; Qin Yan

Background: JARID1B is an H3K4 histone demethylase and an attractive target for cancer therapy. Results: High throughput screen identified novel compounds that can inhibit JARID1B demethylase activity. Conclusion: Drug-like small molecules can be identified to inhibit JARID1B. Significance: The identified JARID1B inhibitors are lead compounds that can be developed into anti-cancer epigenetic drugs. JARID1B (also known as KDM5B or PLU1) is a member of the JARID1 family of histone lysine demethylases responsible for the demethylation of trimethylated lysine 27 in histone H3 (H3K4me3), a mark for actively transcribed genes. JARID1B is overexpressed in several cancers, including breast cancer, prostate cancer, and lung cancer. In addition, JARID1B is required for mammary tumor formation in syngeneic or xenograft mouse models. JARID1B-expressing melanoma cells are associated with increased self-renewal character. Therefore, JARID1B represents an attractive target for cancer therapy. Here we characterized JARID1B using a homogeneous luminescence-based demethylase assay. We then conducted a high throughput screen of over 15,000 small molecules to identify inhibitors of JARID1B. From this screen, we identified several known JmjC histone demethylase inhibitors, including 2,4-pyridinedicarboxylic acid and catechols. More importantly, we identified several novel inhibitors, including 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), which inhibits JARID1B with an IC50 of about 3 μm in vitro. Consistent with this, PBIT treatment inhibited removal of H3K4me3 by JARID1B in cells. Furthermore, this compound inhibited proliferation of cells expressing higher levels of JARID1B. These results suggest that this novel small molecule inhibitor is a lead compound that can be further optimized for cancer therapy.


Nucleic Acids Research | 2013

Physical and functional interaction between yeast Pif1 helicase and Rim1 single-stranded DNA binding protein

Ramanagouda Ramanagoudr-Bhojappa; Lauren P. Blair; Alan J. Tackett; Kevin D. Raney

Pif1 helicase plays various roles in the maintenance of nuclear and mitochondrial genome integrity in most eukaryotes. Here, we used a proteomics approach called isotopic differentiation of interactions as random or targeted to identify specific protein complexes of Saccharomyces cerevisiae Pif1. We identified a stable association between Pif1 and a mitochondrial SSB, Rim1. In vitro co-precipitation experiments using recombinant proteins indicated a direct interaction between Pif1 and Rim1. Fluorescently labeled Rim1 was titrated with Pif1 resulting in an increase in anisotropy and a Kd value of 0.69 µM. Deletion mutagenesis revealed that the OB-fold domain and the C-terminal tail of Rim1 are both involved in interaction with Pif1. However, a Rim1 C-terminal truncation (Rim1ΔC18) exhibited a nearly 4-fold higher Kd value. Rim1 stimulated Pif1 DNA helicase activity by 4- to 5-fold, whereas Rim1ΔC18 stimulated Pif1 by 2-fold. Hence, two regions of Rim1, the OB-fold domain and the C-terminal domain, interact with Pif1. One of these interactions occurs through the N-terminal domain of Pif1 because a deletion mutant of Pif1 (Pif1ΔN) retained interaction with Rim1 but did not exhibit stimulation of helicase activity. In light of our in vivo and in vitro data, and previous work, it is likely that the Rim1–Pif1 interaction plays a role in coordination of their functions in mtDNA metabolism.


Molecular and Cellular Biology | 2009

A Noncanonical Bromodomain in the AAA ATPase Protein Yta7 Directs Chromosomal Positioning and Barrier Chromatin Activity

Angeline Gradolatto; Sherri K. Smart; Stephanie D. Byrum; Lauren P. Blair; Richard S. Rogers; Elizabeth Kolar; Heather Lavender; Signe K. Larson; John D. Aitchison; Sean D. Taverna; Alan J. Tackett

ABSTRACT Saccharomyces cerevisiae Yta7 is a barrier active protein that modulates transcriptional states at the silent mating locus, HMR. Additionally, Yta7 regulates histone gene transcription and has overlapping functions with known histone chaperones. This study focused on deciphering the functional role of the noncanonical Yta7 bromodomain. By use of genetic and epistasis analyses, the Yta7 bromodomain was shown to be necessary for barrier activity at HMR and to have overlapping functions with histone regulators (Asf1 and Spt16). Canonical bromodomains can bind to acetylated lysines on histones; however, the Yta7 bromodomain showed an association with histones that was independent of posttranslational modification. Further investigation showed that regions of Yta7 other than the bromodomain conferred histone association. Chromatin immunoprecipitation-chip analyses revealed that the Yta7 bromodomain was not solely responsible for histone association but was also necessary for proper chromosomal positioning of Yta7. This work demonstrates that the Yta7 bromodomain engages histones for certain cellular functions like barrier chromatin maintenance and particular Spt16/Asf1 cellular pathways of chromatin regulation.


DNA and Cell Biology | 2012

Epigenetic Mechanisms in Commonly Occurring Cancers

Lauren P. Blair; Qin Yan

Cancer is a collection of very complex diseases that share many traits while differing in many ways as well. This makes a universal cure difficult to attain, and it highlights the importance of understanding each type of cancer at a molecular level. Although many strides have been made in identifying the genetic causes for some cancers, we now understand that simple changes in the primary DNA sequence cannot explain the many steps that are necessary to turn a normal cell into a rouge cancer cell. In recent years, some research has shifted to focusing on detailing epigenetic contributions to the development and progression of cancer. These changes occur apart from primary genomic sequences and include DNA methylation, histone modifications, and miRNA expression. Since these epigenetic modifications are reversible, drugs targeting epigenetic changes are becoming more common in clinical settings. Daily discoveries elucidating these complex epigenetic processes are leading to advances in the field of cancer research. These advances, however, come at a rapid and often overwhelming pace. This review specifically summarizes the main epigenetic mechanisms currently documented in solid tumors common in the United States and Europe.


Epigenetics | 2011

MassSQUIRM: An assay for quantitative measurement of lysine demethylase activity.

Lauren P. Blair; Nathan L. Avaritt; Rong Huang; Phillip A. Cole; Sean D. Taverna; Alan J. Tackett

In eukaryotes, DNA is wrapped around proteins called histones and is condensed into chromatin. Post-translational modification of histones can result in changes in gene expression. One of the most well-studied histone modifications is the methylation of lysine 4 on histone H3 (H3K4). This residue can be mono-, di- or tri-methylated and these varying methylation states have been associated with different levels of gene expression. Understanding exactly what the purpose of these methylation states is, in terms of gene expression, has been a topic of much research in recent years. Enzymes that can add (methyltransferases) and remove (demethylases) these modifications are of particular interest. The first demethylase discovered, LSD1, is the most well-classified and has been implicated in contributing to human cancers and to DNA damage response pathways. Currently, there are limited methods for accurately studying the activity of demethylases in vitro or in vivo. In this work, we present MassSQUIRM (mass spectrometric quantitation using isotopic reductive methylation), a quantitative method for studying the activity of demethylases capable of removing mono- and di-methyl marks from lysine residues. We focus specifically on LSD1 due to its potential as a prime therapeutic target for human disease. This quantitative approach will enable better characterization of the activity of LSD1 and other chromatin modifying enzymes in vitro, in vivo or in response to inhibitors.


Science Advances | 2016

KDM5 lysine demethylases are involved in maintenance of 3′UTR length

Lauren P. Blair; Zongzhi Liu; Ramon Lorenzo D. Labitigan; Lizhen Wu; Dinghai Zheng; Zheng Xia; Erica L. Pearson; Fathima I. Nazeer; Jian Cao; Sabine M. Lang; Rachel J. Rines; Samuel G. Mackintosh; Claire Moore; Wei Li; Bin Tian; Alan J. Tackett; Qin Yan

New roles of an epigenetic regulator in RNA processing are discovered, which could be targeted for cancer treatment. The complexity by which cells regulate gene and protein expression is multifaceted and intricate. Regulation of 3′ untranslated region (UTR) processing of mRNA has been shown to play a critical role in development and disease. However, the process by which cells select alternative mRNA forms is not well understood. We discovered that the Saccharomyces cerevisiae lysine demethylase, Jhd2 (also known as KDM5), recruits 3′UTR processing machinery and promotes alteration of 3′UTR length for some genes in a demethylase-dependent manner. Interaction of Jhd2 with both chromatin and RNA suggests that Jhd2 affects selection of polyadenylation sites through a transcription-coupled mechanism. Furthermore, its mammalian homolog KDM5B (also known as JARID1B or PLU1), but not KDM5A (also known as JARID1A or RBP2), promotes shortening of CCND1 transcript in breast cancer cells. Consistent with these results, KDM5B expression correlates with shortened CCND1 in human breast tumor tissues. In contrast, both KDM5A and KDM5B are involved in the lengthening of DICER1. Our findings suggest both a novel role for this family of demethylases and a novel targetable mechanism for 3′UTR processing.


Journal of Visualized Experiments | 2012

Application of MassSQUIRM for Quantitative Measurements of Lysine Demethylase Activity

Lauren P. Blair; Nathan L. Avaritt; Alan J. Tackett

Recently, epigenetic regulators have been discovered as key players in many different diseases (1-3). As a result, these enzymes are prime targets for small molecule studies and drug development( 4). Many epigenetic regulators have only recently been discovered and are still in the process of being classified. Among these enzymes are lysine demethylases which remove methyl groups from lysines on histones and other proteins. Due to the novel nature of this class of enzymes, few assays have been developed to study their activity. This has been a road block to both the classification and high throughput study of histone demethylases. Currently, very few demethylase assays exist. Those that do exist tend to be qualitative in nature and cannot simultaneously discern between the different lysine methylation states (un-, mono-, di- and tri-). Mass spectrometry is commonly used to determine demethylase activity but current mass spectrometric assays do not address whether differentially methylated peptides ionize differently. Differential ionization of methylated peptides makes comparing methylation states difficult and certainly not quantitative (Figure 1A). Thus available assays are not optimized for the comprehensive analysis of demethylase activity. Here we describe a method called MassSQUIRM (mass spectrometric quantitation using isotopic reductive methylation) that is based on reductive methylation of amine groups with deuterated formaldehyde to force all lysines to be di-methylated, thus making them essentially the same chemical species and therefore ionize the same (Figure 1B). The only chemical difference following the reductive methylation is hydrogen and deuterium, which does not affect MALDI ionization efficiencies. The MassSQUIRM assay is specific for demethylase reaction products with un-, mono- or di-methylated lysines. The assay is also applicable to lysine methyltransferases giving the same reaction products. Here, we use a combination of reductive methylation chemistry and MALDI mass spectrometry to measure the activity of LSD1, a lysine demethylase capable of removing di- and mono-methyl groups, on a synthetic peptide substrate (5). This assay is simple and easily amenable to any lab with access to a MALDI mass spectrometer in lab or through a proteomics facility. The assay has ~8-fold dynamic range and is readily scalable to plate format (5).


Molecular Cell | 2006

Yng1 PHD Finger Binding to H3 Trimethylated at K4 Promotes NuA3 HAT Activity at K14 of H3 and Transcription at a Subset of Targeted ORFs

Sean D. Taverna; Serge Ilin; Richard S. Rogers; Jason C. Tanny; Heather Lavender; Haitao Li; Lindsey A. Baker; John Boyle; Lauren P. Blair; Brian T. Chait; Dinshaw J. Patel; John D. Aitchison; Alan J. Tackett; C. David Allis

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Alan J. Tackett

University of Arkansas for Medical Sciences

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Heather Lavender

University of Arkansas for Medical Sciences

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Kevin D. Raney

University of Arkansas for Medical Sciences

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