Copy - FOXA1 TRANSCRIPTION FACTOR

FOX A1TRANSCRIPTION FACTOR

BY HERITAGE AFOLABI

INDEX

1. Family History

4. Development in Mice

5. Experiments !

2. What is FOXA1 ?

3. ER FOX A1 COMPLEX

6. Possible treatment

A LITTLE FAMILY HISTORY...

• 90s- was trying to find transcription factors responsible for the tissue specific expression of genes defining liver developemnt and function
• Discovered HNF-3A
• Expression was enriched in liver tissue
• was essential for liver Morphogenesis

James E. Darnell

Arround the same time..

• Drisophila Forkhead (fkh) gene sequence was determined
• essential for Drisophila development - Detlef Weigal
• High homology with hnf3a bidning domain discovered after aligning DNA
• lack zinc finger motifs- new class of transcription factors

What is FOX A1 ?

• AKA hepatocyte nuclear factor 3-alpha
• Member of Forkhead box (FOX) protein family

• Acts as a Pioneer factor for many receptors

-> estrogen receptor-α isoform (ER)

• Promotes endocrine-resistant cell growth (breast cells)

• regulates a variety of tissues during embryogenesis and early life

ER FOXA1 COMPLEX

• FOXA1 opens consenced chomatin
• ER binds at enhancer
• Chromatin loop forms to bring ER within close proximetry
• Transcription of growth promoting associated genes

FOXA1 IN DEVELOPMENT IN MICE

• FOXA1 RNA detected in the late primative streak stage in midline endodorm

-> Immunohistochemical localisation

• Later on in ventral floor plate, notochord and gut
• In adults- mesoderm and ectroderm derived tissues
• Evidence for role in developmental specification

Image depicting different stages of muce embryogenesis

immunohistochemical localisation of foxa1

• immunostained embryos with antibody for FOXA1

and antibody for FOXA2 in order to localise the protiens

• liver stomach lung, dorsal epethelium of tongue

• Prove secfifcity of antibodies
• HeLA cell Lycates transfected with pcDNA3.1 or

pcDNA-mFOXA1

• FOX A2 done with rat cDNA
• subjected to electrophresis
• immunoblotted with respective antibodies
• no reaction cross over
• detected FOXa1 and reactive fragment (Mr-25000)
• detected FOXa2 and reactive frgment

impact of FOXA1 on mammary gland morphogenesis

Stage 1

New method

Stage 2

mice embryo has homozygous deletion of FOXa1

Use mammary gland transplantation processes instead

At birth, is similar to wild type but dies soon after due to hypoglycemia and dehydration

POSSIBLE TREATMENT

• Many women who have ER related breast cancer become resistant to ER targetting medication
• need to create treatment that targets the ER complex as a whole
• FOXA1 a very important target for medicines as the complex cannot work without it
• Opportunity for new effective drugs

Refrences

[1]G. M. Bernardo and R. A. Keri, “FOXA1: a transcription factor with parallel functions in development and cancer,” Bioscience Reports, vol. 32, no. 2, pp. 113–130, Oct. 2011, doi: 10.1042/bsr20110046.[2]X. Fu, R. Pereira, C. De Angelis, and J. Veeraraghavan, “FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer,” PNAS, vol. 116, no. 52, pp. 1–2, Nov. 2019, Accessed: Nov. 15, 2022. [Online]. Available: https://www.pnas.org/doi/suppl/10.1073/pnas.1911584116 [3]D. D. Seachrist, L. J. Anstine, and R. A. Keri, “FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer,” Cancers, vol. 13, no. 20, p. 3, Oct. 2021, doi: 10.3390/cancers13205205. [4]V. Besnard, S. E. Wert, W. M. Hull, and J. A. Whitsett, “Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues,” Gene Expression Patterns, vol. 5, no. 2, pp. 195–197, Dec. 2004, doi: 10.1016/j.modgep.2004.08.006. [5]P. P.L Tam and R. R Behringer, “Mouse gastrulation: the formation of a mammalian body plan,” Mechanisms of Development, vol. 68, no. 1–2, p. 6, Nov. 1997, doi: 10.1016/S0925-4773(97)00123-8.

Thank You!