Computational modeling of gene-specific transcriptional repression, activation and chromatin interactions in leukemogenesis by LASSO-regularized logistic regression

ABSTRACT The reciprocal expression of GATA-1 and GATA-2 during hematopoiesis is an important determinant of red blood cell development. Whereas Gata2 is preferentially transcribed early in hematopoiesis, elevated GATA-1 levels result in GATA-1 occupancy at sites upstream of the Gata2 locus and transcriptional repression. GATA-2 occupies these sites in the transcriptionally active locus, suggesting that a “GATA switch” abrogates GATA-2-mediated positive autoregulation. Chromatin immunoprecipitation (ChIP) coupled with genomic microarray analysis and quantitative ChIP analysis with GATA-1-null cells expressing an estrogen receptor ligand binding domain fusion to GATA-1 revealed additional GATA switches 77 kb upstream of Gata2 and within intron 4 at +9.5 kb. Despite indistinguishable GATA-1 occupancy at −77 kb and +9.5 kb versus other GATA switch sites, GATA-1 functioned uniquely at the different regions. GATA-1 induced histone deacetylation at and near Gata2 but not at the −77 kb region. The −77 kb region, which was DNase I hypersensitive in both active and inactive states, conferred equivalent enhancer activities in GATA-1- and GATA-2-expressing cells. By contrast, the +9.5 kb region exhibited considerably stronger enhancer activity in GATA-2- than in GATA-1-expressing cells, and other GATA switch sites were active only in GATA-1- or GATA-2-expressing cells. Chromosome conformation capture analysis demonstrated higher-order interactions between the −77 kb region and Gata2 in the active and repressed states. These results indicate that dispersed GATA factor complexes function via long-range chromatin interactions and qualitatively distinct activities to regulate Gata2 transcription.

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PRC1 catalytic activity is central to Polycomb system function

10.1101/667667 ◽

2019 ◽

Cited By ~ 2

Author(s):

Neil P. Blackledge ◽

Nadezda A. Fursova ◽

Jessica R. Kelley ◽

Miles K. Huseyin ◽

Angelika Feldmann ◽

...

Keyword(s):

Catalytic Activity ◽

Transcriptional Repression ◽

Target Genes ◽

Embryonic Stem ◽

Chromatin Domain ◽

System Function ◽

Target Site Selection ◽

Chromatin Interactions ◽

Mutation System ◽

New Evidence

SummaryThe Polycomb repressive system is an essential chromatin-based regulator of gene expression. Despite being extensively studied, how its target genes are selected and whether its histone modifying activities are required for transcriptional repression remains controversial. Here, we directly test the requirement for PRC1 catalytic activity in Polycomb system function. We demonstrate that a mutation widely used to disrupt PRC1 catalysis is hypomorphic, complicating the interpretation of previous studies. To overcome this, we develop a new inducible mutation system in embryonic stem cells that completely ablates PRC1 catalytic activity, revealing that catalysis by PRC1 drives Polycomb chromatin domain formation and higher-order chromatin interactions. In the absence of catalysis, we uncover the primary DNA-based targeting determinants that direct Polycomb target site selection. Finally, we discover that Polycomb-mediated gene repression requires PRC1 catalytic activity. Together these discoveries provide compelling new evidence supporting a PRC1-initiated pathway for Polycomb system function in gene regulation.

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Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia

10.1101/2020.03.05.979070 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ping Wang ◽

Zhonghui Tang ◽

Byoungkoo Lee ◽

Jacqueline Jufen Zhu ◽

Liuyang Cai ◽

...

Keyword(s):

Transcriptional Repression ◽

Molecular Mechanisms ◽

Myeloid Cells ◽

Leukemia Cells ◽

Myeloid Differentiation ◽

3D Genome ◽

Chromatin Interactions ◽

Genome Wide ◽

Interaction Domains

AbstractBackgroundAcute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML/RARα in leukemogenesis remains largely unknown.ResultsUsing an inducible system, we comprehensively analyzed the 3D genome organization in myeloid cells and its reorganization after PML/RARα induction, and performed additional analyses in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediates extensive chromatin interactions genome-wide. Globally, it redefines the chromatin topology of the myeloid genome toward a more condensed configuration in APL cells; locally, it intrudes RNAPII-associated interaction domains, interrupts myeloid-specific transcription factors binding at enhancers and super-enhancers, and leads to transcriptional repression of genes critical for myeloid differentiation and maturation.ConclusionsOur results not only provide novel topological insights for the roles of PML/RARα in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.

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Computational Modeling of Cognition and Behavior

10.1017/cbo9781316272503 ◽

2018 ◽

Cited By ~ 32

Author(s):

Simon Farrell ◽

Stephan Lewandowsky

Keyword(s):

Computational Modeling ◽

And Behavior

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How Useful is the Power Law of Practice for Recognizing Practice in Concentration Tests?

European Journal of Psychological Assessment ◽

10.1027/1015-5759.23.3.157 ◽

2007 ◽

Vol 23 (3) ◽

pp. 157-165 ◽

Cited By ~ 4

Author(s):

Carmen Hagemeister

Keyword(s):

Logistic Regression ◽

Reaction Time ◽

Power Law ◽

Error Rate ◽

Reaction Times ◽

Practice Effect ◽

Practice Effects ◽

Rate Decrease ◽

Small Practice

Abstract. When concentration tests are completed repeatedly, reaction time and error rate decrease considerably, but the underlying ability does not improve. In order to overcome this validity problem this study aimed to test if the practice effect between tests and within tests can be useful in determining whether persons have already completed this test. The power law of practice postulates that practice effects are greater in unpracticed than in practiced persons. Two experiments were carried out in which the participants completed the same tests at the beginning and at the end of two test sessions set about 3 days apart. In both experiments, the logistic regression could indeed classify persons according to previous practice through the practice effect between the tests at the beginning and at the end of the session, and, less well but still significantly, through the practice effect within the first test of the session. Further analyses showed that the practice effects correlated more highly with the initial performance than was to be expected for mathematical reasons; typically persons with long reaction times have larger practice effects. Thus, small practice effects alone do not allow one to conclude that a person has worked on the test before.

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Perceived Effectiveness of Random Testing for Alcohol and Drugs in the Australian Aviation Community

Aviation Psychology and Applied Human Factors ◽

10.1027/2192-0923/a000031 ◽

2012 ◽

Vol 2 (2) ◽

pp. 72-81

Author(s):

Christina M. Rudin-Brown ◽

Eve Mitsopoulos-Rubens ◽

Michael G. Lenné

Keyword(s):

Logistic Regression ◽

Online Survey ◽

Random Testing ◽

Regression Analyses ◽

Perceived Effectiveness ◽

Student Pilots ◽

Alcohol And Drugs ◽

Positive Attitudes ◽

One Year ◽

Alcohol And Other Drugs

Random testing for alcohol and other drugs (AODs) in individuals who perform safety-sensitive activities as part of their aviation role was introduced in Australia in April 2009. One year later, an online survey (N = 2,226) was conducted to investigate attitudes, behaviors, and knowledge regarding random testing and to gauge perceptions regarding its effectiveness. Private, recreational, and student pilots were less likely than industry personnel to report being aware of the requirement (86.5% versus 97.1%), to have undergone testing (76.5% versus 96.1%), and to know of others who had undergone testing (39.9% versus 84.3%), and they had more positive attitudes toward random testing than industry personnel. However, logistic regression analyses indicated that random testing is more effective at deterring AOD use among industry personnel.

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