Human Gene Expression:
Introduction
"Within the intricate dance of our genes ,
there is a symphony of expression ,
orchestrating the melody of life ."
Annunziato, A. (2008) DNA Packaging: Nucleosomes and Chromatin.Nature Education1(1):26
Chromosomes are composed of DNA tightly-wound around histones
• Certain proteins compact chromosomal DNA into the microscopic space of
the eukaryotic nucleus. These proteins are called histones, and the resulting
DNA-protein complex is called chromatin.
• Nucleosome: DNA wound twice around 8 histones
• Histone releasesfrom DNA during DNA replication and gene expression
The Central Dogma
DNA
Contains the genetic information that codes for proteins and other cellular functions.
RNA
Intermediary molecule that is transcribed from DNA and translated to form proteins.
Protein
Functional molecule made up of amino acids.
Performs various cellular functions, including catalyzing chemical reactions and providing structural support.
Pramanik, D., Shelake, R. M., Kim, M. J., & Kim, J. Y. (2021).
Overview of the Central Dogma of Molecular Biology
and Processes Involved
in Relaying the Flow of
Genetic Information.
McManus, J., Cheng, Z., & Vogel, C. (2015). Molecular BioSystems,11(10), 2680-2689.
Annotating the central dogma of molecular biology
Possible outcomes of different rates of synthesis and degradation. Different rates of synthesis and
degradation can result in different concentrations and concentration changes over time
Gene Regulation
Transcriptional Regulation
Involves controlling the amount of mRNA being produced from a particular gene. Can be achieved through the use of promoters, enhancers, and transcription factors.
Post-transcriptional Regulation
Involves controlling the processing and stability of mRNA. Can be achieved through mRNA splicing, capping, and polyadenylation, as well as through the use of miRNA and siRNA.
Importance of Regulation
Allows cells to respond to changes in the environment, maintain homeostasis, and prevent the expression of unnecessary or harmful genes.
Transcription is affected by:
• Where promoter located in relation to nucleosomes
• Genes with heterochrome typically not transcribed
• Chemical modification to histones and DNA
•Promoter Location in Relation to Nucleosomes:
•Explanation: The arrangement of nucleosomes, which are structures made of DNA wound around histone proteins, can influence gene transcription. If a promoter region (the region where RNA polymerase binds to initiate
transcription) is tightly wrapped in nucleosomes, it may impede the access of transcriptional machinery to the DNA.
•Example:The tumor suppressor gene p53 has a promoter region that can be influenced by nucleosome
positioning. If nucleosomes obstruct the promoter, it may limit the transcription of p53, which plays a crucial role in preventing the formation of cancerous cells.
•Genes with Heterochromatin Typically Not Transcribed:
•Explanation: Heterochromatin is a tightly packed form of chromatin, often associated with gene silencing. In heterochromatin, the DNA is less accessible for transcriptional machinery, leading to reduced or inhibited gene transcription.
•Example:In humans, the inactivation of one X chromosome in females is an example of heterochromatin-mediated gene silencing. The X-inactivation process ensures that only one X chromosome is actively transcribed in each cell, preventing the overexpression of X-linked genes.
•Chemical Modifications to Histones and DNA:
•Explanation: Chemical modifications, such as acetylation, methylation, and phosphorylation, to histones and DNA can influence the structure of chromatin. These modifications can either promote or inhibit gene transcription by altering the accessibility of DNA to transcriptional machinery.
•Example:Histone acetylation is associated with open chromatin structure and active transcription. For instance, acetylation of histones in the promoter region of the p21 gene can enhance its transcription. On the other hand, DNA methylation is often associated with gene repression. Hypermethylation of the promoter region of tumor suppressor genes, like BRCA1, can lead to their silencing in certain cancers.
Histone acetylation
• Addition of acetyl group (-COCH
3) to histone tail
• Neutralizes positive charge of tail -->
consequences: no binding to
neighboring nucleosomes and genes available for transcription
• Requires enzymes: may be part of transcription factors binding to
promoter
Histone methylation
• Adds methyl group (-CH 3 ) to histone tails
• Promotes chromatin condensation
Histone phosphorylation
• Promotes unfolding of chromatin
• Many signals may work together
DNA methylation
• Addition of methyl group to base (~cytosine)
o Inactivated X chromosome highly methylated
o Long term inactivation of genes
• Multiple mechanisms may work together
o Certain proteins binding to methyl groups recruit histone deacetylation enzymes
▪ Both act to increase
condensation of chromatin
Histone phosphorylation
• Promotes unfolding of chromatin
• Many signals may work together
Regulation of transcription initiation
Gene Expression "On"
1 Activation of Gene Expression
Involves upregulating transcription of a particular gene. Can be achieved through the use of positive regulatory elements.
2 Examples of Gene Expression "On" in Human Cells
Includes the process of cellular differentiation and the response to stimuli such as stress and hormones.
Gene Expression "Off"
1 Repression of Gene Expression
Involves downregulating transcription of a particular gene. Can be achieved through the use of negative regulatory elements.
2 Examples of Gene Expression "Off" in Human Cells
Includes the process of cellular quiescence and the response to inhibitory signals.
Impact of Gene Expression Changes
Disease and Aberrant Gene Expression
Aberrant gene expression can lead to various diseases, including cancer and genetic
disorders related to gene expression.
Technological Advances in Studying Gene Expression
Recent advances in transcriptomics, including microarray analysis and RNA sequencing, as well as in gene editing using CRISPR/Cas9, have enabled researchers to study gene expression on a large scale and modify it for research and therapeutic purposes.
Future Directions
Improvement of Disease Diagnostic and Treatment
By better understanding how gene expression is regulated and how it impacts cellular processes, we can gain insights into various diseases and develop more effective diagnostic and treatment strategies.
Gene Editing
The increasing power and precision of gene editing technologies hold promise for curing genetic diseases and developing new therapies. However, ethical considerations must be taken into account as we explore these avenues.
