What controls gene expression?
A typical animal genome encodes approximately 20,000 genes. However, not all genes are expressed in all cell types and gene expression often changes drastically over time, such as during embryonic development. Adding further complexity is that the control of gene expression can occur at multiple steps: accessibility of a gene to activating transcription factors, transcription initiation, transcript elongation, splicing of the pre-mRNA, as well as post-transcriptional regulation. At the same time, alternative promoter usage and splicing can greatly increase the diversity of transcripts subjected to regulation. Not surprisingly, disruption at any of these steps can contribute to or cause human disease. MCCB researchers focus on multiple aspects of gene expression in their studies. This work includes a focus on gene expression in the context of normal settings, such as how embryonic stem cells maintain their ability to renew and retain their pluripotency, as well as transcriptional pathways that are known to be blocked in the context of cancer. Research includes particular emphasis on “epigenetic” modes of regulation, such as how accessibility to transcription factor binding sites is controlled and how non-coding RNAs contribute to this process. Several labs also investigate the important role of small non-coding RNAs in post-transcriptional control of gene expression, as well as how splicing is regulated.
Click below to see more details on how MCCB labs are studying the control of gene expression.
One of the main goals of the research carried out in the Bach lab is to understand mechanisms controlling gene expression during mammalian embryogenesis. The research investigates how the dynamic regulation of transcription factor activity orchestrates cell fate decisions during development and how disturbances can lead to human disease. More recently, the lab also studies how female cells inactivate one of their two X chromosomes in a process called X-chromosome inactivation (XCI), a form of epigenetic gene silencing.
- Güngör et al., 2007 Proteasomal selection of multiprotein complexes recruited by LIM-HD transcription factors. Proc Natl Acad Sci USA 104, 15000-5
- Shin et al., 2010. Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice. Nature 467, 977-81
- Shin et al., 2014. RLIM is dispensable for X-chromosome inactivation in the mouse embryonic epiblast. Nature 511, 86-9
The Baehrecke Laboratory studies how steroid hormones, which typically act by directly modulating gene expression through their nuclear receptors, control distinct types of cell responses within animal cells and tissues. Researchers in the laboratory combine genetics, genome profiling technologies and proteomics to screen for genes and pathways that control cell survival and cell death. These data are used to develop a comprehensive understanding of the genetic regulatory network that controls cell survival and cell death.
- Lee et al. (2003) Genome-wide analyses of steroid- and radiation-triggered programmed cell death in Drosophila. Curr Biol, 13(4):350-7.
- McPhee et al. (2013) Identification of factors that function in Drosophila salivary gland cell death during development using proteomics. Cell Death Differ, 20(2):218-25.
- Nelson et al. (2014) miR-14 regulates autophagy during developmental cell death by targeting ip3-kinase 2. Mol Cell, 56(3):376-88.
Cell proliferation is controlled by a tightly-regulated transcriptional program, which ensures that cells only proceed through the cell division cycle when they receive the appropriate signals. This program is established by a network of conserved transcription factors, many of which are mutated or misregulated in cancer cells. The Benanti Lab uses yeast as a model system to study the connections between cell cycle-regulatory transcription factors, and to determine how phosphorylation and ubiquitination coordinate their activities. These studies are complemented by work in human cells aimed at understanding the regulation of oncogenic transcription factors that are core components of the cell cycle network.
The actions of most factors that regulate gene expression, including transcription factors, long non-coding RNAs, and others, are modulated by the underlying packaging of each eukaryotic gene into chromatin. The relative "openness" of chromatin controls the access of each of these factors to DNA. Consequently, careful control of chromatin structure is necessary to establish and maintain cell type-specific gene expression patterns. The Fazzio lab studies how chromatin structure is controlled in stem cells, adult cells, and how chromatin structure is perturbed in cancer cells.
- Yildirim et al. (2011) Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell, 147(7):1498-510.
- Chen et al. (2013) Hdac6 regulates Tip60-p400 function in stem cells. Elife. 2013 Dec 3;2:e01557
- Hainer et al. (2015) Suppression of pervasive noncoding transcription in embryonic stem cells by esBAF. Genes Dev. 29(4):362-78.
The Green lab has a broad interest in the mechanisms that regulate gene expression in eukaryotes, and the role of gene expression in various human disease states. They pursue this interest through the use of molecular biology, molecular genetic, and biochemical approaches involving diverse experimental systems that bear on different aspects of gene regulation. Much of eukaryotic gene expression is regulated at the transcriptional level, and the lab has made seminal contributions in transcription factor discovery, understanding the role of basic transcription factors in gene regulation, and elucidating transcription activation mechanisms. Recently, the lab has studied transcriptional regulation in cancer development and has made significant contributions to our understanding of oncogene-directed epigenetic silencing.
- Gazin et al. (2007) An elaborate pathway required for Ras-mediated epigenetic silencing. Nature, 449(7165):1073-7.
- Hart et al. (2007) Initiation of zebrafish haematopoiesis by the TATA-box-binding protein-related factor Trf3. Nature, 450(7172):1082-5.
- Maston et al. (2012) Non-canonical TAF complexes regulate active promoters in human embryonic stem cells. Elife. 1:e00068.
Mitochondrial and metabolic perturbations result in numerous alterations in gene expression. The Haynes Lab focuses on the mitochondrial UPR, an intra-cellular stress response that modulates gene expression to repair and recover mitochondrial activity. We have uncovered a novel form of transcriptional regulation based on organelle partitioning of a single transcription factor (ATFS-1 in worms, ATF5 in mammals) that allows cells to evaluate mitochondrial function or dysfunction and adjust transcription accordingly. Researchers in the laboratory examine how ATFS-1 is further regulated and integrates with other metabolic stress response pathways to promote survival during mitochondrial dysfunction.
- Nargund AN*, Pellegrino MW*, Fiorese CJ, Baker BM, Haynes CM. (2012) Mitochondrial import of ATFS-1 regulates mitochondrial UPR activation. Science. Aug 3;337(6094): 587-90.
- Nargund AN, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM. (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPRmt. Molecular Cell. April 2;58(1):123-33.
- Haynes CM, Fiorese CJ, Lin YF.(2013) Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded protein response and beyond. Trends in Cell Biology. July;23(7): 311-318.
The Kaufman Lab has a long-term interest in proteins that deliver histones to DNA with an emphasis on the DNA-replication linked histone deposition factor termed Chromatin Assembly Factor-1 (CAF-1). In their most recent studies, the Kaufman Lab has discovered multiple nucleolar proteins associated with the CAF-1 p150 subunit. Notably, p150 depletion causes redistribution of multiple nucleolar proteins and reduces nucleolar association with repetitive element-containing loci. Furthermore, the nucleolar functions of p150 are separable from its interactions with the other subunits of the CAF-1 complex. Together, these data define novel functions for a separable domain of the p150 protein, regulating protein and DNA interactions at the nucleolus.
The Mao laboratory studies transcriptional regulation mediated by several signaling pathways (Hedgehog, Wnt and Hippo) in tissue stem cells, progenitors, and transformed cancer cells. They use RNAseq, ChIPseq and Bioinformatics to investigate how tissue- or cancer-specific transcriptional output of these pathways is achieved.
The Socolovsky lab has identified an epigenetic switch that controls the transition from self-renewal to differentiation in erythroid progenitors. Interestingly, this cell fate decision is orchestrated by the cell cycle and is associated with an unusual process in which there is global loss of genomicDNA methylation, the first such instance to be identified in somatic cells.
- Pop et al (2010) A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1 and S-phase progression. PLoS Biol. 2010 Sep 21;8(9)
- Shearstone JR, Pop R, Bock C, Boyle P, Meissner A, Socolovsky M. Global DNA demethylation during mouse erythropoiesis in vivo. Science. 2011 Nov 11;334(6057):799-802.
The Wolfe Lab focuses on multiple aspects of gene expression, including transcriptional and post-transcriptional control. They are also interested in developing new tools for targeted gene regulation. In addition, the Wolfe Lab is part of the Innate Immune Gene Regulatory Project, a collaborative effort to understand the regulatory pathways that underpin the response of Dendritic cells to pathogens. Regarding post-transcriptional control of gene expression, they are focused on understanding the role of miR-375 in pancreatic endocrine cell development using zebrafish as a model.
- Zhu L et al. (2011) FlyFactorSurvey: a database of Drosophila transcription factor binding specificities determined using the bacterial one-hybrid system. Nucleic Acids Res. 39(Database issue):D111-7.
- Enuameh et al (2013) Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants. Genome Res. 23(6):928-40.
- Kearns et al. (2014) Cas9 effector-mediated regulation of transcription and differentiation in human pluripotent stem cells. Development, 141(1):219-23.