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Phát hiện quan trọng về vô sinh ở nam giới giúp tìm ra những phương pháp điều trị mới

By Sally Robertson, B.Sc.Dec 16 2019

Các nhà nghiên cứu ở Đại học Y Khoa Penn đã tạo ra một mô hình đột biến mới cho phép họ xác định các khiếm khuyết trong biểu mô tinh trùng gây ra vô sinh ở nam giới.

Image Credit: Yurchanka Siarhei / Shutterstock.com

Việc phát triển này, được miêu tả gần đây trên tạp chí Developmental Cell, có thể dẫn đến những phương pháp mới để sửa chữa những tinh trùng khuyết tật.

Một trong tám cặp vợ chồng gặp khó khăn trong việc thụ thai, và gần 25% những trường hợp này, vấn đề tiềm ẩn là vô sinh nam. Nghiên cứu trong 10 năm qua đã quy kết sự vô sinh này là do tinh trùng bị lỗi không “đuổi” các histone ra khỏi ADN trong quá trình phát triển. Histone là các protein trong nhiễm sắc chất  đóng gói ADN, bật tắt các gen, và thay thế chúng bằng các protein nhỏ hơn nhiều được gọi là các protamin mà có thể đóng gói ADN vào tinh trùng đúng cách.

Tuy nhiên, các nhà nghiên cứu chưa hiểu đầy đủ các cơ chế ẩn dưới sự trục xuất này hoặc chính xác nơi chúng diễn ra trong ADN tinh trùng.

Bây giờ các nhà nghiên cứu của Đại học Y Khoa Penn, Lacey Luense, Shelley Berger và Daniel Och đã sử dụng các kỹ thuật giải trình tự ADN trên toàn bộ bộ gen mới để tìm ra chính xác nơi các histone được giữ lại trong bộ gen và xác định một gen quan trọng có tên Gcn5 điều chỉnh quá trình.

Sau đó, họ đã thiết kế một mô hình đột biến với phiên bản Gcn5 đột biến, cho phép họ theo dõi chặt chẽ các khiếm khuyết từ giai đoạn đầu phát triển tinh trùng thông qua thụ tinh và trở đi.

Một phát triển quan trọng

Phát triển quan trọng này không chỉ cải thiện hiểu biết về vô sinh nam và các phương pháp tiềm năng để đảo ngược nó, mà còn cả các đột biến biểu sinh có thể được truyền vào phôi từ người nam

Ngoại di truyền, các thay đổi kế thừa trong bộ gen không được giải mã bởi AND, có ảnh hưởng mạnh mẽ đến cách tinh trùng được tạo thành. “Đối với những đàn ông bị vô sinh không rõ nguyên nhân, mọi thứ trông có vẻ bình thường đối với các bác sĩ: số lượng tinh trùng bình thường, khả năng vận động bình thường. Tuy nhiên, họ vẫn có thể có những vấn đề về thụ thai,” tác giả đầu tiên Luense nói.

Luense cho biết một lời giải thích tiềm năng là các histone ở sai vị trí, điều này có thể ảnh hưởng đến tinh trùng và sau đó phát triển sớm: “Bây giờ, chúng tôi có một mô hình thực sự tốt để nghiên cứu những gì xảy ra khi bạn không loại bỏ các histone một cách thích hợp trong tinh trùng và những gì có thể trông giống như trong phôi. “

Với sự hiểu biết rằng histones bị giữ lại ảnh hưởng đến khả năng sinh sản và phát triển phôi, các nhà khoa học quan tâm đến việc xác định vị trí gen của chúng để chúng có thể được sử dụng cho nghiên cứu trong tương lai và cuối cùng là phát triển các phương pháp điều trị.

Các nghiên cứu trước đây cho ra những kết quả mâu thuẫn.

Các nghiên cứu trước đây đã tạo ra kết quả mâu thuẫn. Một số nghiên cứu sử dụng công nghệ gọi là giải trình tự MNase đã xác định vị trí của các histone được giữ lại như trên các chất kích thích gen quan trọng, trong khi nghiên cứu khác sử dụng cùng một công cụ, đã xác định chúng tại các lần lặp lại DNA và trong cái gọi là “sa mạc gen”, nơi chúng ít tham gia hơn vào quy định.

Nghiên cứu hiện tại cho thấy cả hai mô hình đều đúng

Những dữ liệu không nhất quán này đã dẫn đến tranh cãi giữa các nhà nghiên cứu trong lĩnh vực này, Luense nói. Tuy nhiên, nghiên cứu hiện tại cho thấy rằng cả hai mô hình được mô tả, trên thực tế, đều đúng.

“Chúng tôi tìm thấy các histone trên các gen có vẻ quan trọng đối với sự phát triển của phôi, nhưng chúng tôi cũng tìm thấy chúng ở các yếu tố lặp đi lặp lại, những nơi cần phải tắt và để ngăn chặn sự biểu hiện của các khu vực này trong phôi. “

Nhà nghiên cứu ĐH Y Khoa Penn, Lacey Luense

Để nghiên cứu, nhóm nghiên cứu đã sử dụng một công nghệ mới hơn, nhanh hơn và chính xác hơn gọi là giải trình tự ATAC để theo dõi các histone tại các vị trí duy nhất trên bộ gen trong suốt giai đoạn đầu và cuối của quá trình phát triển tinh trùng ở chuột. Cách tiếp cận này có thể xác định các khu vực của bộ gen nơi các histone được giữ lại và sau đó cắt và gắn thẻ DNA đó để có thể giải trình tự.

Các nhà nghiên cứu phát hiện ra rằng những con chuột được thiết kế để có gen đột biến Gcn5 có khả năng sinh sản rất thấp. Họ cũng phát hiện ra rằng các histone được giữ lại trong tinh trùng khỏe mạnh tương quan với vị trí của các histone trong phôi rất sớm, điều này hỗ trợ cho suy nghĩ rằng thông tin biểu sinh được truyền qua các histone của cha.

Một cơ hội để tìm kiếm các phương pháp điều trị tiềm năng

Sử dụng mô hình đột biến, các nhà nghiên cứu có thể nghiên cứu chi tiết các cơ chế ẩn giấu dưới quỹ đạo của tinh trùng bị khiếm khuyết và có ảnh hưởng gì đến sự phát triển của phôi thai. Nó cũng cung cấp một cơ hội để điều tra các mục tiêu điều trị tiềm năng.

Berger chỉ ra rằng, hiện tại, gánh nặng của IVF và các công nghệ hỗ trợ sinh sản khác thuộc về phụ nữ và ngay cả khi vô sinh là do yếu tố nam giới, vẫn là những phụ nữ phải trải qua các thủ thuật và tiêm hormone.

“Bây giờ hãy tưởng tượng bạn có thể áp dụng phương pháp trị liệu biểu sinh để thay đổi mức độ histone và protamine ở nam giới trước khi tạo phôi?” cô ấy nói. “Đó là một trong những câu hỏi chúng tôi muốn khám phá và mô hình này sẽ cho phép chúng tôi di chuyển theo hướng đó.”

Nhóm nghiên cứu cho biết những hạn chế với phôi người đã dẫn đến việc thiếu nghiên cứu tổng thể về vô sinh và vai trò của biểu sinh của người cha đối với sự phát triển phôi, trong đó nhấn mạnh tầm quan trọng của các nghiên cứu như thế này.

“Có rất nhiều yếu tố khác nhau có thể làm thay đổi biểu mô tinh trùng: chế độ ăn uống, thuốc, rượu chẳng hạn,” Luense nói. “Chúng tôi mới bắt đầu hiểu làm thế nào điều đó có thể ảnh hưởng đến đứa trẻ và ảnh hưởng đến sự phát triển. Những nghiên cứu cơ bản ban đầu mà chúng tôi đang thực hiện rất quan trọng, vì vậy chúng tôi có thể hiểu rõ hơn điều gì thúc đẩy các đột biến biểu sinh này.”

Nguồn:

Penn researchers uncover defective sperm epigenome that leads to male infertility. EurekAlert. Available from https://www.eurekalert.org/emb_releases/2019-12/uops-pru121319.php

(Nguồn: https://www.news-medical.net/news/20191216/Important-discovery-about-male-infertility-could-lead-to-new-treatments.aspx)

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