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7.342 | Fall 2017 | Undergraduate

# How To Build An Animal: Cell Fate and Identity in Development and Disease

Handouts and notes are provided for a subset of the lectures.

WEEK # | TOPICS | LECTURE SUMMARIES
--- | --- | ---

1 | Class introduction | Introductions: Instructors and students Overview of the syllabus and expectations Overview of primary research papers and how to find them Introduction to the field How biology defines cell “identity” and “fate”—what constitutes a cell’s identity? Regulation of gene expression (transcriptional, post-transcriptional, translational) Week 1 handout (PDF)

2 | Potency and pluripotent stem cells | A critical feature of a given cell’s identity is its potency: The degree to which a cell is able to give rise to multiple differentiated cell lineages. Characterization of pluripotent stem cells, which are often derived from embryonic cells, has provided insight into the molecular features that permit pluripotency in early development. This week we will read a classic paper that helped define “embryonic stem cells” as well as a more recent research report that characterized fundamental molecular signatures of pluripotent stem cells. Week 2 handout (PDF)

3 | Signatures and mechanisms of pluripotency: Transcriptional networks | Following the discovery and initial characterization of pluripotent stem cells, several open questions remained on how pluripotent stem cells are derived and maintain their potency. Some of these mechanisms have been elucidated through functional characterization of specific pluripotency factors, such as the core transcription factor Nanog and the histone methyltransferase Wdr5. The two papers we will read this week focus on these essential factors, which work to maintain a specific transcriptional state and chromatin environment (i.e., the spatial organization of the genome within the nucleus) that is conducive for pluripotency. Week 3 handout (PDF)

4 | Signatures and mechanisms of pluripotency: Bivalent chromatin domains | The pluripotent transcriptional network is made up of genes that promote stem cell identity. While maintenance of this transcriptional network is essential for stem cell identity, pluripotent cells are also poised to differentiate into somatic cell types. This week we will examine two pieces of literature that investigate the presence of bivalent chromatin domains in stem cells and germ cells. Bivalent chromatin domains are stretches of DNA (often containing genes) with both activating and repressive epigenetic markers, which allows the cell to rapidly adjust its transcriptional activity upon somatic differentiation. This week we will read the first paper to describe bivalent chromatin domains and their significance in pluripotency, and a more recent paper that expands our understanding of how bivalent chromatin domains are conserved across species in germ cells.

5 | Germ cell identity | In contrast to pluripotent stem cells, which are undifferentiated cells that maintain the capability to give rise to any cell type, germ cells are specialized cells that develop either as eggs or sperm. There are major differences between germ cells and somatic cells (haploid as opposed to diploid, for example), and germ cell identity and differentiation is massively distinct from the identity and differentiation of either pluripotent stem cells or differentiated somatic cells. However, like pluripotent stem cells, germ cells must maintain their developmental potential to give rise to an entirely new organism. This week, we will read papers that discuss how cells within the early embryo are guided toward a germ cell fate rather than a somatic fate, using both intrinsic and extrinsic mechanisms. We will study examples of the two prevailing models of germ cell formation: 1) preformation via inheritance of maternally supplied germ plasm in flies and 2) induction via signaling from extraembryonic tissue in mice.

6 | Reprogramming of germ cells and stem cells | With better understanding of certain cell fates and identities, researchers have been able to assess the extent to which cell fate and identity may be guided in vivo, within the totipotent germ line, or in vitro, through expression of master transcription factors in pluripotent stem cells. We will first discuss a paper showing the reprogramming of worm germ cells into specific neuronal subtypes through forced expression of terminal transcription factors. We will then examine the transcriptional requirements needed to form functional mouse germ cells in vitro.

7 | Reprogramming soma by pioneer transcription factors | While it is generally thought that a cell’s developmental potential becomes restricted as it commits to a somatic fate, forced expression of specific transcription factors can induce fate-switching in somatic cells. Termed pioneer transcription factors, these factors are thought to activate certain transcriptional programs by binding the promoters of genes necessary for somatic development. This week we will read a classic paper that identified the first pioneer transcription factor, MyoD, the expression of which causes fibroblasts to switch to a muscle cell fate. We will then explore the molecular events that follow the expression of pioneer transcription factors and lead to reprogramming of fibroblasts to neurons. Week 7 handout (PDF)

8 | Defining hematopoietic identities: Part 1 | The immune system is composed of numerous specialized cell types called hematopoietic blood cells, and the process through which these cells differentiate from a stem cell to their final cell fate is called hematopoiesis. Given the diversity in the types of hematopoietic cells and their involvement in numerous diseases, such as autoimmune disease and cancer, hematopoietic cell-fate decisions and identity have been an area of intense research for decades. This week we will read papers that were critical in the early understanding of how common hematopoietic progenitor cells give rise to their specialized, differentiated daughter cells. Week 8 handout (PDF)

9 | Defining hematopoietic identities: Part 2 | With the advance of high-throughput sequencing of RNA from single cells, researchers have been able to characterize genome-wide transcriptional differences between cell types, rather than the differential expression of only a few genes. Current transcriptional profiling methods have allowed for expanded and more precise categorizations of hematopoietic cells and thus refinement in how cell identity is defined. This week’s reading highlights more recent research that demonstrates the greater resolution with which we can classify cell types via genome-wide transcriptional profiling and single-cell sequencing. The first paper utilizes single-cell RNA sequencing to identify novel subsets of differentiated hematopoietic cells. The second paper more closely examines the transcriptional profiles of early progenitor cells, including hematopoietic stem cells, and challenges earlier paradigms of hematopoietic differentiation.

10 | Regulatory mechanisms for immune cell identity: Chromatin and transcription factors | Different hematopoietic cell types are distinguished by gene expression patterns. How do these extensive gene expression profiles arise? This week we will discuss papers with two alternate mechanisms for influencing cell fate: Master regulators and chromatin remodeling. Master regulators are transcription factors that are typically at the top of a hierarchical cascade of gene expression activity, such that activity from the single transcription factor is crucial for a cell type’s particular gene expression pattern. Chromatin remodeling entails altering how DNA itself is packaged and structured around histone proteins, making the DNA accessible or inaccessible to various transcription factors. The first paper for this week concerns the interaction between two master regulators in zebrafish to guide hematopoietic identity. This week’s second paper focuses on changes to chromatin in the development of T cells, which are key cells in the immune system that coordinate specific, targeted responses to pathogens like viruses and bacteria.

11 | Regulatory mechanisms for immune cell identity: Cell signaling | In addition to internal changes within cells that influence cell fate (such as master regulator transcription factors and chromatin remodeling), external signals also play an important role in guiding cell fate and identity. These signals are often small proteins secreted by other immune cells called cytokines. This week we will read different examples of how cell signaling is able to guide cell identity. Both of the papers this week focus on hematopoietic cells from the adaptive immune system: B cells, which recognize antibodies, and T cells, which bind to other immune cells that have identified pathogens in the body. In the first example, we will read about how B cells require signaling from the cytokine interleukin-7 to properly develop. In the second example, we will read about how naive CD4+ T cell differentiation is influenced by the surrounding cytokine environment.

﻿12 | Disorders of cell identity: The reproductive tract and germ cell identity | Differentiated somatic cells, once thought to be fixed in their developmental potential, are much more plastic than previously appreciated and utilize mechanisms of chromatin organization to prevent their acquisition of other cell fates. This week we will look in worms and the mammalian gonad as examples of how the expression of chromatin factors can influence the fate of somatic cell types and lead to fate-switching when removed, leading to drastic effects on organismal health.

﻿﻿13 | Disorders of cell identity: Hematopoiesis | Genes that play important roles in the differentiation of hematopoietic lineages are often mutated in blood cancers, i.e., forms of leukemia. This week we will examine two variations of leukemia that result from mutations in crucial B cell or T cell differentiation genes. By analyzing the specific phenotypes that arise from these oncogenic mutations, researchers can characterize the roles that different genes play in immune cell differentiation. While both papers focus on oncogenes, i.e., genes that contribute to cancer when mutated, each study utilizes a different approach. The first paper identifies this genes through a genome-wide screen of patients with acute lymphoblastic leukemia, while the second paper targets specific oncogenes and demonstrates their importance in T cell differentiation in mouse models.

14 | Cellular reprogramming and therapeutics | A major goal of regenerative medicine is to direct the formation of specific tissue types that can be transplanted back into patients who have lost tissue function. The two papers we will discuss this week focus on generating highly differentiated somatic cell types, pancreatic β cells (for the treatment of Type I diabetes) and cardiomyocytes (as a potential therapy for heart disease), from pluripotent cells using either cocktails of transcription factors or small molecules. These papers highlight the various methods researchers are currently using to drive specific cell types in vitro and also raise the question: How similar are these cells to their in vivo counterparts?

15 | Oral presentations and evaluations | Students will give their final presentations, complete course evaluations, and discuss the course (good and bad).

## Course Info

##### Instructor

- Dr. Laura V Blanton

##### Departments

- Biology

##### As Taught In

Fall 2017

##### Level

Undergraduate

##### Topics

- Health and Medicine
  - Biomedicine
- Science
  - Biology
    - Cell Biology
    - Developmental Biology
    - Stem Cells

##### Learning Resource Types

assignment Presentation Assignments
assignment Written Assignments

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