Characterization of Histone H2A Functional Domains Important for Regulation of the DNA Damage Response

DNA double strand breaks represent deleterious lesions which can either be caused by environmental or endogenous sources of DNA damage. Efficient DNA damage response which ensures repair of these lesions is therefore critical for maintenance of genomic stability. The repair happens in the context of chromatin, a three-dimensional nucleoprotein complex consisting of DNA, histones and associated proteins. As such, mechanisms that modulate chromatin structure, many of which involve the histone component of chromatin, have been shown to play a role in regulation of the DNA damage response. In my thesis work I characterize two conserved histone H2A functional domains that are required for normal response to DNA damage. In the first part of my thesis, my collaborators and I demonstrate that Tetrahymena major histone H2A.S contains an H2A.X variant-specific SQ motif within its C-terminal tail, providing the first description of this region in ciliated protozoa. The function of the SQ motif is mediated by post-translational phosphorylation of the conserved serine which is essential for normal progression through Tetrahymena life cycle, and in particular, meiosis. This study provides the first evidence for the existence of meiotic DSBs in Tetrahymena and defines the time interval of meiotic recombination in this organism. In the second part of my thesis, I describe a functional domain which encodes a unique and previously unrecognized role for the histone H2A Nterminal tail in the DNA damage response in S. cerevisiae. A DNA damage survival property exists within the conserved SRS motif spanning residues 17-19 of a single turn α-helical region in the H2A tail, known as the ‘knuckle’. I demonstrate that the SRS motif is required for efficient checkpoint recovery following successful repair, a function independent of post-translational modifications. Another contribution of histone H2A in S. cerevisiae, specific to the MMS induced DNA damage response, is provided by the three amino-terminal lysines which appear to be functionally redundant. My collaborators and I demonstrate that in vivo two of the lysines, H2A K4 and H2A K7, are acetylated individually as well as together , and identify the third lysine, H2A K13, as a novel acetylation site in S. cerevisiae

Validation of the short version (TLS-15) of the triangular love scale (TLS-45) across 37 languages

Love is a phenomenon that occurs across the world and affects many aspects of human life, including the choice of, and process of bonding with, a romantic partner. Thus, developing a reliable and valid measure of love experiences is crucial. One of the most popular tools to quantify love is Sternberg’s 45-item Triangular Love Scale (TLS-45), which measures three love components: intimacy, passion, and commitment. However, our literature review reveals that most studies (64%) use a broad variety of shortened versions of the TLS-45. Here, aiming to achieve scientific consensus and improve the reliability, comparability, and generalizability of results across studies, we developed a short version of the scale—the TLS-15—comprised of 15 items with 5-point, rather than 9-point, response scales. In Study 1 (N = 7,332), we re-analyzed secondary data from a large-scale multinational study that validated the original TLS-45 to establish whether the scale could be truncated. In Study 2 (N = 307), we provided evidence for the three-factor structure of the TLS-15 and its reliability. Study 3 (N = 413) confirmed convergent validity and test–retest stability of the TLS-15. Study 4 (N = 60,311) presented a large-scale validation across 37 linguistic versions of the TLS-15 on a cross-cultural sample spanning every continent of the globe. The overall results provide support for the reliability, validity, and cross-cultural invariance of the TLS-15, which can be used as a measure of love components—either separately or jointly as a three-factor measure.2-s2.0-8517840985238038856Aralı

The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons

The histone deacetylase HDAC2, which negatively regulates synaptic gene expression and neuronal plasticity, is upregulated in Alzheimer's disease (AD) patients and mouse models. Therapeutics targeting HDAC2 hold promise for ameliorating AD-related cognitive impairment; however, attempts to generate HDAC2-specific inhibitors have failed. Here, we take an integrative genomics approach to identify proteins that mediate HDAC2 recruitment to synaptic plasticity genes. Functional screening revealed that knockdown of the transcription factor Sp3 phenocopied HDAC2 knockdown and that Sp3 facilitated recruitment of HDAC2 to synaptic genes. Importantly, like HDAC2, Sp3 expression was elevated in AD patients and mouse models, where Sp3 knockdown ameliorated synaptic dysfunction. Furthermore, exogenous expression of an HDAC2 fragment containing the Sp3-binding domain restored synaptic plasticity and memory in a mouse model with severe neurodegeneration. Our findings indicate that targeting the HDAC2-Sp3 complex could enhance cognitive function without affecting HDAC2 function in other processes

Social and moral psychology of COVID-19 across 69 countries

The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables

Psychological Science Accelerator: A Promising Resource for Clinical Psychological Science

The Psychological Science Accelerator (PSA) is an international collaborative network of psychological scientists that facilitates rigorous and generalizable research. In this chapter, we describe how the PSA can help clinical psychologists and clinical psychological science more broadly. We first describe the PSA and outline how individual clinical psychologists can use the PSA as a helpful resource in numerous capacities: leading or contributing to clinical research or research with clinical relevance, building collaborative relationships, obtaining experience and expertise, and learning about systems and tools, particularly those related to open science practices, that they can adapt to their own research. We then describe how the PSA supports rigor and transparency at each stage of the research process. Finally, we discuss the challenges of the PSA’s large, collaborative approach to research

Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2 R306C mutation prevents MeCP2 from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex; however, the neuronal function of HDAC3 is incompletely understood. We found that neuronal deletion of Hdac3 in mice elicited abnormal locomotor coordination, sociability and cognition. Transcriptional and chromatin profiling revealed that HDAC3 positively regulated a subset of genes and was recruited to active gene promoters via MeCP2. HDAC3-associated promoters were enriched for the FOXO transcription factors, and FOXO acetylation was elevated in Hdac3 knockout (KO) and Mecp2 KO neurons. Human RTT-patient-derived MECP2 R306C neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2 R306C cells to generate isogenic controls rescued HDAC3-FOXO-mediated impairments in gene expression. Our data suggest that HDAC3 interaction with MeCP2 positively regulates a subset of neuronal genes through FOXO deacetylation, and disruption of HDAC3 contributes to cognitive and social impairment.National Institutes of Health (U.S.) (Grant NS78839

Social and moral psychology of COVID-19 across 69 countries

The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables

Problematic use of the internet during the COVID-19 pandemic: Good practices and mental health recommendations.

With the onset of the COVID-19 pandemic and the accelerated spread of the SARS-CoV-2 virus came jurisdictional limitations on mobility of citizens and distinct alterations in their daily routines. Confined to their homes, many people increased their overall internet use, with problematic use of the internet (PUI) becoming a potential reason for increased mental health concerns. Our narrative review summarizes information on the extent of PUI during the pandemic, by focusing on three types: online gaming, gambling and pornography viewing. We conclude by providing guidance for mental health professionals and those affected by PUI (with an outline of immediate research priorities and best therapeutic approaches), as well as for the general public (with an overview of safe and preventative practices)

HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease

DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5XFAD mouse model of Alzheimer’s disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5XFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration