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T-Cell Development: Transcriptional and Epigenetic Regulation in BCL11B Activation

Deichmann, Julia LU (2018) FYTM03 20181
Department of Astronomy and Theoretical Physics
Abstract
Haematopoietic stem cells are the source of all blood components including T-cells. When the T-cell programme is initiated in these cells, the expression of T-cell associated genes such as TCF7 is up-regulated, while genes opposing this fate are turned off. Subsequently, epigenetic marks on the gene BCL11B and its regulatory elements, disabling the expression of the gene, are removed and the transcription factor, which is crucial for the commitment to the T-cell lineage, is expressed with a delay. However, size and number of regulatory regions of BCL11B are unknown.

Single cell data available of the expression of T-cell specific and opposing genes, as well as BCL11B were used to construct a time series of gene expression during T-cell... (More)
Haematopoietic stem cells are the source of all blood components including T-cells. When the T-cell programme is initiated in these cells, the expression of T-cell associated genes such as TCF7 is up-regulated, while genes opposing this fate are turned off. Subsequently, epigenetic marks on the gene BCL11B and its regulatory elements, disabling the expression of the gene, are removed and the transcription factor, which is crucial for the commitment to the T-cell lineage, is expressed with a delay. However, size and number of regulatory regions of BCL11B are unknown.

Single cell data available of the expression of T-cell specific and opposing genes, as well as BCL11B were used to construct a time series of gene expression during T-cell development, which exhibits a down-regulation of the genes opposing T-cell fate. Moreover, the time series displays a switch in the expression level of T-cell associated genes and a delayed onset of BCL11B expression. The interactions between the examined transcription factors are summarised in a gene regulatory network. Its parameters were optimised to fit the time series, showing that model and data are in agreement regarding the essential characteristics of the system. Afterwards, a stochastic simulation of the regulatory network was included in an epigenetic toy model describing the demethylation and transcription of BCL11B. It leads to the conclusion that the time until a region is demethylated increases with its size. Furthermore, it hints towards a threshold in the amount of unmethylated DNA that is required for a transcription factor to bind, offering a delayed expression of BCL11B. (Less)
Popular Abstract
T Cells - Fighters of our Immune System

T cells are a vital part of our immune system. But there are also diseases linked to them. To fight those diseases, we need to understand the process in which T cells develop. Ultimately, this might enable us to prevent their dysfunction.

The immune system is our body police, protecting us against disease by detecting and fighting viruses and bacteria. Some of its policemen are called T cells, a type of white blood cell. When presented a fragment of a known infectious agent, called antigen, an immune response is triggered which is then executed by different types of T cells. One of these subunits are killer T cells. They are responsible for killing infected cells. Helper T cells instead... (More)
T Cells - Fighters of our Immune System

T cells are a vital part of our immune system. But there are also diseases linked to them. To fight those diseases, we need to understand the process in which T cells develop. Ultimately, this might enable us to prevent their dysfunction.

The immune system is our body police, protecting us against disease by detecting and fighting viruses and bacteria. Some of its policemen are called T cells, a type of white blood cell. When presented a fragment of a known infectious agent, called antigen, an immune response is triggered which is then executed by different types of T cells. One of these subunits are killer T cells. They are responsible for killing infected cells. Helper T cells instead coordinate other cells fighting the virus; they enhance the activity of the killer T cells, and they mobilize macrophages, which are cells that eat the infectious intruders. Moreover, when T cells replicate, some of their daughter cells become memory cells, to whom they pass on which pathogens they have encountered, so that an immediate, strong response can be triggered when detected again.

It is clear, that the immune system is of great importance to keep us alive. And while usually doing a good job at this, defects can occur and result in drastic consequences. Partial T cell deficiency or even complete insufficiency, due to gene mutations, make the body vulnerable, since it can not defend itself against harmful intruders. Moreover, there are blood cancers that can arise from T cells.

To prevent diseases of the immune system linked to T cells, it is important to understand how these cells form. They develop from progenitor cells; cells that initially have several possible fates. From there, they run through specific steps of development until becoming specialized as a T cell. If we would understand this process in detail and could identify all the players involved, we could also find out what can go wrong and what consequences that has. The ultimate goal is then to use this knowledge in order to find a way to fix the damage, or even to prevent it. This would enable our body police to fulfil its duty, protecting us against disease, successfully and at full speed. (Less)
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author
Deichmann, Julia LU
supervisor
organization
course
FYTM03 20181
year
type
H2 - Master's Degree (Two Years)
subject
keywords
T cell, immune system, BCL11B, TCF7, epigenetics, methylation, gene regulation
language
English
id
8945226
date added to LUP
2018-06-08 08:53:59
date last changed
2018-06-08 08:53:59
@misc{8945226,
  abstract     = {Haematopoietic stem cells are the source of all blood components including T-cells. When the T-cell programme is initiated in these cells, the expression of T-cell associated genes such as TCF7 is up-regulated, while genes opposing this fate are turned off. Subsequently, epigenetic marks on the gene BCL11B and its regulatory elements, disabling the expression of the gene, are removed and the transcription factor, which is crucial for the commitment to the T-cell lineage, is expressed with a delay. However, size and number of regulatory regions of BCL11B are unknown. 

Single cell data available of the expression of T-cell specific and opposing genes, as well as BCL11B were used to construct a time series of gene expression during T-cell development, which exhibits a down-regulation of the genes opposing T-cell fate. Moreover, the time series displays a switch in the expression level of T-cell associated genes and a delayed onset of BCL11B expression. The interactions between the examined transcription factors are summarised in a gene regulatory network. Its parameters were optimised to fit the time series, showing that model and data are in agreement regarding the essential characteristics of the system. Afterwards, a stochastic simulation of the regulatory network was included in an epigenetic toy model describing the demethylation and transcription of BCL11B. It leads to the conclusion that the time until a region is demethylated increases with its size. Furthermore, it hints towards a threshold in the amount of unmethylated DNA that is required for a transcription factor to bind, offering a delayed expression of BCL11B.},
  author       = {Deichmann, Julia},
  keyword      = {T cell,immune system,BCL11B,TCF7,epigenetics,methylation,gene regulation},
  language     = {eng},
  note         = {Student Paper},
  title        = {T-Cell Development: Transcriptional and Epigenetic Regulation in BCL11B Activation},
  year         = {2018},
}