Zahra Bahrami-Nejad

Bio: Zahra Bahrami-Nejad is an academic researcher from Stanford University. The author has contributed to research in topics: Adipogenesis & Progenitor cell. The author has an hindex of 4, co-authored 13 publications receiving 118 citations.

Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling.

Abstract: The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling β-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems.

Chromatin-Remodeling Complex SWI/SNF Controls Multidrug Resistance by Transcriptionally Regulating the Drug Efflux Pump ABCB1.

Abstract: Anthracyclines are among the most effective yet most toxic drugs used in the oncology clinic. The nucleosome-remodeling SWI/SNF complex, a potent tumor suppressor, is thought to promote sensitivity to anthracyclines by recruiting topoisomerase IIa (TOP2A) to DNA and increasing double-strand breaks. In this study, we discovered a novel mechanism through which SWI/SNF influences resistance to the widely used anthracycline doxorubicin based on the use of a forward genetic screen in haploid human cells, followed by a rigorous single and double-mutant epistasis analysis using CRISPR/Cas9-mediated engineering. Doxorubicin resistance conferred by loss of the SMARCB1 subunit of the SWI/SNF complex was caused by transcriptional upregulation of a single gene, encoding the multidrug resistance pump ABCB1. Remarkably, both ABCB1 upregulation and doxorubicin resistance caused by SMARCB1 loss were dependent on the function of SMARCA4, a catalytic subunit of the SWI/SNF complex. We propose that residual SWI/SNF complexes lacking SMARCB1 are vital determinants of drug sensitivity, not just to TOP2A-targeted agents, but to the much broader range of cancer drugs effluxed by ABCB1. Cancer Res; 76(19); 5810-21. ©2016 AACR.

Molecular competition in G1 controls when cells simultaneously commit to terminally differentiate and exit the cell-cycle

Abstract: Terminal differentiation is essential for the development and maintenance of tissues in all multi-cellular organisms and is associated with a permanent exit from the cell cycle. Failure to permanently exit the cell cycle can result in cancer and disease. However, the molecular mechanisms and timing that coordinates differentiation commitment and cell cycle exit are not yet understood. Here using adipogenesis as a model system to track differentiation commitment in live cells, we show that a rapid switch mechanism engages exclusively in G1 to trigger a simultaneous commitment to differentiate and permanently exit from the cell cycle. We identify a signal integration mechanism whereby the strengths of both mitogen and differentiation stimuli control a molecular competition between cyclin D1 and PPARG-induced expression of the CDK inhibitor p21 which in turn regulates if and when the differentiation switch is triggered and when the proliferative window closes. In this way, the differentiation control system is able to couple mitogen and differentiation stimuli to sustain a long-term balance between terminally differentiating cells and maintaining the progenitor cell pool, a parameter of critical importance for enabling proper development of tissue domains and organs.

Adipogenesis and metabolic health

Abstract: Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it constitutes a public health issue of major proportion. The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy) or by the formation of new adipocytes from precursor differentiation in the process of adipogenesis (hyperplasia). Notably, adipocyte expansion through adipogenesis can offset the negative metabolic effects of obesity, and the mechanisms and regulators of this adaptive process are now emerging. Over the past several years, we have learned a considerable amount about how adipocyte fate is determined and how adipogenesis is regulated by signalling and systemic factors. We have also gained appreciation that the adipogenic niche can influence tissue adipogenic capability. Approaches aimed at increasing adipogenesis over adipocyte hypertrophy can now be explored as a means to treat metabolic diseases.

Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling.

Abstract: Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.

Genomics of circadian rhythms in health and disease.

Abstract: Circadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including the regulation of sleep, metabolism, and the immune system. Here, we review advances in understanding the genetic regulation of sleep through the circadian system, as well as the impact of dysregulated gene expression on metabolic function. We also review recent studies that have begun to unravel the circadian clock’s role in controlling the cardiovascular and nervous systems, gut microbiota, cancer, and aging. Such circadian control of these systems relies, in part, on transcriptional regulation, with recent evidence for genome-wide regulation of the clock through circadian chromosome organization. These novel insights into the genomic regulation of human physiology provide opportunities for the discovery of improved treatment strategies and new understanding of the biological underpinnings of human disease.

Wnt signalling: conquering complexity

Abstract: The history of the Wnt pathway is an adventure that takes us from mice and flies to frogs, zebrafish and beyond, sketching the outlines of a molecular signalling cascade along the way. Here, we specifically highlight the instrumental role that developmental biology has played throughout. We take the reader on a journey, starting with developmental genetics studies that identified some of the main molecular players, through developmental model organisms that helped unravel their biochemical function and cell biological activities. Culminating in complex analyses of stem cell fate and dynamic tissue growth, these efforts beautifully illustrate how different disciplines provided missing pieces of a puzzle. Together, they have shaped our mechanistic understanding of the Wnt pathway as a conserved signalling process in development and disease. Today, researchers are still uncovering additional roles for Wnts and other members of this multifaceted signal transduction pathway, opening up promising new avenues for clinical applications.