🎚️ Lecture 6: Regulation of the Activity of Transcription Factors

Lipid Hormone Regulation of Transcription Factors

Direct Regulation
 Transcription factor activity can be directly regulated by lipid hormones

Hormone Signaling
 A cell sends a signal to other cells by secreting a lipid-soluble hormone

Hormone Entry and Receptors
 Lipid-soluble hormones diffuse through the plasma membrane
 They bind a dedicated class of proteins
 These are lipid-hormone receptors also called transcriptional activators

Cytoplasmic Receptors
 Some receptors are located in the cytoplasm
 Hormone binding forms a receptor–hormone complex
 The complex moves to the nucleus if not already there
 It becomes an active transcription factor
 It binds specific response elements of genes
 This regulates gene expression

Nuclear Receptors
 Other receptors are located in the nucleus
 Hormone binding changes their activity

Shared Features
 Lipid-hormone receptors and transcription activators share significant homology

Lipid-Soluble Hormones and Nuclear Receptors

Figure 8-42 Examples
 Examples of lipid-soluble hormones that bind to nuclear receptors

Retinoic Acid

Cortisol

Thyroxine

Nuclear Receptor Transcription Factors Structure

Figure 8-42
 General design of transcription factors in the nuclear-receptor superfamily

Overall Structure
 N terminus to C terminus
 General primary structure is shared

Variable Region
 Located at N terminus
 Length is 100–500 amino acids
 Low amino acid identity
 Identity range 0

DNA-Binding Domain
 Length is 68 amino acids
 Responsible for binding DNA
 Amino acid identity is high
 Identity range 42–94%

Ligand-Binding Domain
 Located toward C terminus
 Length is 225–285 amino acids
 Binds hormone ligand
 Amino acid identity range 15–57%

Examples of Nuclear Receptors
 Estrogen receptor ER
 Progesterone receptor PR
 Glucocorticoid receptor GR
 Thyroxine receptor TR
 Retinoic acid receptor RAR

DNA Response Elements for Nuclear Receptors

Figure 8-43
 Consensus sequences of DNA response elements that bind nuclear receptors

Glucocorticoid Response Element GRE
 DNA response element that binds the glucocorticoid receptor

Estrogen Response Element ERE
 DNA response element that binds the estrogen receptor

Vitamin D3 Response Element VDRE
 DNA response element that binds the vitamin D3 receptor

Thyroid Hormone Response Element TRE
 DNA response element that binds the thyroid hormone receptor

Retinoic Acid Response Element RARE
 DNA response element that binds the retinoic acid receptor

Cytoplasmic Hormone Receptors and Nuclear Translocation

Cytoplasmic Receptors
 For hormones that cannot enter the nucleus, their receptors are in the cytoplasm

Chaperone Proteins
 Receptors are kept out of the nucleus by chaperone proteins
 Chaperones block nuclear import

Hormone Binding
 Hormone binding makes chaperones detach
 This exposes the Nuclear Localization Signal NLS

Nuclear Import and Activation
 The receptor–hormone complex is imported into the nucleus
 DNA binding occurs
 This results in gene activation

Domains
 AD = Activation Domain
 DBD = DNA-Binding Domain
 LBD = Ligand-Binding Domain

Eukaryotic Activators and Repressors

DNA Binding
 Activators and repressors usually bind directly to DNA in promoters or enhancers

Gene Expression Regulation
 From these positions they recruit multi-subunit co-activator or co-repressor complexes
 These complexes modulate chromatin structure or interact with the Mediator and General Transcription Factors

Activators
 Stimulate assembly of preinitiation complexes
 Move nucleosomes away from promoters

Specificity
 A cell must produce the specific set of activators required for a specific promoter or enhancer to express a particular gene

Repressors
 Often work by building repressive chromatin structures

Mechanisms
 Chromatin remodeling can lead to transcriptional repression or activation

Recall

Epigenetic Regulation and Pioneer Transcription Factors

Epigenetic Regulation
 Transcription in eukaryotes occurs on chromatin
 Chromatin must open for transcription to proceed

Pioneer Transcription Factors
 Establish and maintain open chromatin structure
 Do not directly activate transcription

Gene Off
 Chromatin is closed
 Repressors and chromatin co-activators are present
 Ac = acetylation, Me = methylation

Open Chromatin
 Pioneer transcription factors help keep chromatin open
 Allows transcription to occur

Histones and the Histone Code

Nucleosome Structure
 The nucleosome is built of 8 histones
 Two of each: H2A, H2B, H3, H4

Histone Core Domains
 Core domains form the highly structured nucleosome

Histone N-Termini
 N-termini are unstructured and protrude from the core
 They are modified by post-translational modifications PTMs

Histone Code
 PTMs dictate the function of the DNA wrapped around the nucleosome
 Collectively, these modifications are called the “histone code”

The Nucleosome: Histone Tail Modifications

Types of Modifications
 Acetylation Ac
 Phosphorylation P
 Ubiquitination Ub
 Methylation Me

Histone H1
 Not part of the nucleosome
 Associates with DNA between individual nucleosomes

Histone Codes

Diversity
 There are thousands of possible histone codes
 Different combinations of PTMs on histone tails create diverse regulatory signals